Trifluoromethyl-containing phenylsulfonamide beta amyloid inhibitors

ABSTRACT

A compound of Formula (I), or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, wherein Formula (I) has the structure: 
     
       
         
         
             
             
         
       
     
     is provided, wherein R 1 -R 7  are defined herein. These compounds are useful in medicaments for treating a disease selected from the group consisting of Alzheimer&#39;s disease, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, mild cognitive impairment (MCI) and Down&#39;s syndrome, in a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 11/788,349, filed Apr. 19, 2007, which claims the benefit of the priority of U.S. Provisional Patent Application No. 60/793,852, filed Apr. 21, 2006, now expired.

BACKGROUND OF THE INVENTION

This invention relates to inhibitors of beta amyloid production, which have utility in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia (loss of memory) in the elderly. The main pathological lesions of AD found in the brain consist of extracellular deposits of beta amyloid protein in the form of plaques and angiopathy and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein. Recent evidence has revealed that elevated beta amyloid levels in the brain not only precede tau pathology but also correlate with cognitive decline. Further suggesting a causative role for beta amyloid in AD, recent studies have shown that aggregated beta amyloid is toxic to neurons in cell culture.

Beta amyloid protein is composed mainly of 39-42 amino acid peptides and is produced from a larger precursor protein called amyloid precursor protein (APP) by the sequential action of the proteases beta and gamma secretase. Although rare, cases of early onset AD have been attributed to genetic mutations in APP that lead to an overproduction of either total beta amyloid protein or its more aggregation-prone 42 amino acid isoform. Furthermore, people with Down's syndrome possess an extra chromosome that contains the gene that encodes APP and thus have elevated beta amyloid levels and invariably develop AD later in life.

Heterocyclic sulfonamide inhibitors of beta amyloid production have been described. U.S. Pat. Nos. 6,878,742 (2005) and 6,610,734 (2003). Fluoro-and trifluoroalkyl-containing heterocyclic sulfonamide inhibitors of beta amyloid production have also been described in US Patent Application Publication No. US2004/0198778.

There continues to be a need for compositions useful in inhibiting beta amyloid production and in the treatment of the effects of Alzheimer's disease (AD).

SUMMARY OF THE INVENTION

In one aspect, a compound of Formula (I), or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, is provided wherein Formula (I) has the structure:

wherein R₁ through R₇ are defined herein.

In another aspect, a pharmaceutical composition is provided which contains a compound described herein and a physiologically compatible carrier.

In yet a further aspect, a method of inhibiting beta amyloid production in a subject is provided by delivering a compound or composition described herein.

In still a further aspect, a method of treating a disease selected from among Alzheimer's disease, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, mild cognitive impairment (MCI) and Down's syndrome is provided.

Other aspects and advantages of the invention will be apparent from the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (I), their pharmaceutical formulations, and their use in inhibiting beta amyloid production in patients susceptible to, or suffering from, AD or other diseases resulting from elevated levels of beta amyloid protein in the brain are described. The compounds of formula (I) include pharmaceutically acceptable salts and/or hydrates or prodrugs thereof:

wherein, R₁ through R₅ are independently selected from H, halogen, lower alkyl, lower alkoxy, OCF₃, OCF₂H, CF₃, NO₂, CN, CH₃CO, and SCH₃; R₆ and R₇ are independently selected from lower alkyl and CF₃(CH₂) ; n is independently selected from 0, 1, 2 and 3, provided that at least one of R₆ and R₇ are CF₃(CH₂)_(n).

In one embodiment, R₁, R₂, R₄, and R₅ are H; R₃ is halogen, R₆ and R₇ are CF₃ with S-stereochemistry at the chiral center.

The term “alkyl” is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms (e.g., C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, or C₁₀), such as one to eight carbon atoms (e.g., C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈), one to six carbon atoms (e.g., C₁, C₂, C₃, C₄, C₅, or C₆), or one to four carbon atoms (e.g., C₁, C₂, C₃, or C₄). The term “lower alkyl” refers to straight- and branched-chain saturated aliphatic hydrocarbon groups having one to six carbon atoms (e.g., C₁, C₂, C₃, C₄, C₅, or C₆), desirably one to four carbon atoms (e.g., C₁, C₂, C₃, or C₄).

The term “alkoxy” is used herein to refer to the O(alkyl) group, where the point of attachment is through the oxygen-atom and the alkyl can be optionally substituted.

The term “halogen” refers to Cl, Br, F, or I.

The pharmaceutically acceptable salts are those derived from such organic and inorganic bases as: sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, diethanolamine, ethylenediamine and similarly known acceptable bases. Prodrugs of the compounds may be produced and utilized by one skilled in the art.

Synthesis

The compounds can be prepared in a number of ways well known to one skilled in the art of organic synthesis. More particularly, the compounds can be prepared using the methods described below, together with synthetic methods known in the synthetic organic arts or variations of these methods by one skilled in the art. Desirable methods include, but are not limited to, those outlined below.

A first method of preparation includes reaction of a 1,2-amino alcohol II with the appropriate sulfonyl halide in the presence of a base, such as triethylamine, in a suitable solvent to afford compounds of formula I (Scheme 1).

A second method of preparation involves reaction of an a-amino acid or ester III with the appropriate sulfonyl halide in the presence of a base, such as triethylamine, in a suitable solvent to afford compounds of formula IV (Scheme 2). The intermediate N-sulfonyl acid IV (Rx=H) can be converted to the corresponding primary alcohol I utilizing standard methodology such as LiAIH₄, B₂H₆ or cyanuric chloride/NaBH₄. The intermediate N-sulfonyl ester IV (R_(x)=alkyl, Bn) can also be reduced to the corresponding primary alcohol I utilizing standard methodology such as LiAlH₄.

In a variation of the second method to prepare the primary alcohols, an a-amino acid or ester (or N-protected derivative thereof V is first converted to the corresponding primary 1 ,2-aminoalcohol VI (using the methodology outlined in Scheme 2), which is subsequently, after deprotection (if necessary), reacted with the appropriate sulfonyl halide (Scheme 3) to afford compounds of formula I.

For preparation of compounds derived from unnatural a-amino acids containing beta branching in the amino acid side chain, a method of preparation based on the work of Hruby (Tet. Lett. 38: 5135-5138 (1997)) is outlined in Scheme 4. This route entails formation of the a,β-unsaturated amide X of an Evans chiral auxiliary from bromoacetyl bromide VII via a Homer-Emmons reaction sequence, followed by conjugate addition of an organocuprate, trapping of the resulting enolate anion XI with NBS, displacement of bromide XII with azide anion to afford XIII, followed by reduction to the 1,2-amino alcohol and subsequent sulfonylation to afford the target compound XIV.

An alternate preparation of sulfonamides derived from unnatural 1,2-amino alcohols utilizes the Bucherer modification of the Strecker a-amino acid synthesis (Scheme 5). In this route, an aldehyde XV is reacted with cyanide anion and ammonium carbonate to afford the hydantoin XVI which is hydrolyzed to the a-amino acid XVII. This compound is then reduced to XVIII and sulfonylated to afford the desired compounds of formula XIX. Alternatively the intermediate amino acid XVII can be first sulfonylated to afford XX, which is then reduced to XIX. The racemic products XVI, XVII, XVIII, XIX or XX can be resolved to the desired S enantiomer using standard methodology by one skilled in the art.

Another method of preparing chirally pure N-sulfonyl 1,2-amino alcohols derived from a-amino acids is outlined in Scheme 6. This method initially involves formation of the a,β-unsaturated amide XXIII of the Evans chiral auxiliary from bromoacetyl bromide VII via a Horner-Emmons reaction sequence. Conjugate addition of an organocuprate and protonation of the resulting enolate anion affords XXIV, which is then converted to the corresponding enolate and electrophilically aminated with trisyl azide to afford the key intermediate XXV (J. Am. Chem. Soc. 109: 6881-6883 (1987)). Tne azide intermediate XXV is then hydrolyzed to the a-azido acid XXVI and reduced to the chirally pure a-amino acid XXVII which can be converted to the corresponding N-sulfonyl 1,2-amino alcohols by methods previously described above (e.g., Scheme 2).

Finally, chirally pure a-amino acids XXX, one of the possible synthetic precursors of chiral N-sulfonyl 2-amino alcohols XXXII, can also be prepared utilizing asymmetric variants of the Strecker a-amino acid synthesis as outlined in Scheme 7 (J. Org. Chem. 61:440-441 (1996)) and Scheme 8 (J. Org. Chem. 54:1055-1062 (1989)).

Still other suitable methods may be selected by one of skill in the art. For example, another suitable method for selectively N-sulfonylation of 2-amino trifluoroalkyl substituted alcohols has been described in the co-owned U.S. Provisional Patent Application No. 60/774,300, filed Feb. 17, 2006. Methods for preparing sulfonamide substituted alcohols and intermediates thereof are described in co-owned U.S. Provisional Patent Application No. 60/774,453, also filed Feb. 17, 2006. Further, methods for production of chirally pure amino alcohol intermediates, derivatives thereof, and uses thereof are described in US Provisional Patent Application No. 60/793,874, filed Apr. 21, 2006. The methods described in these applications are hereby incorporated by reference and may be adapted for use as described herein.

Pharmaceutical Formulation

The compounds may be administered to a subject by any desirable route, taking into consideration the specific condition for which it has been selected. By subject is meant any suitable mammal, including humans, domestic animals (e.g., canines and felines), and livestock, which have been recognized as having or at risk of having one or more of the conditions for which modulation of beta amyloid levels is desirable. Thus, the compounds are useful for treatment and/or prevention of a number of human and veterinary conditions. As used herein, “prevention” encompasses prevention of symptoms in a subject who has been identified as at risk for the condition, but has not yet been diagnosed with the same and/or who has not yet presented any symptoms thereof.

These compounds may be delivered or administered by any suitable route of delivery, e.g., oral, intravenous, subcutaneous, intramuscular, sublingual, intracranial, epidural, intratracheal, rectal (suppository), vaginal, among others. Most desirably, the compounds are delivered orally or by a suitable parenteral route. The compounds may be formulated in combination with conventional pharmaceutical carriers that are physiologically compatible. Optionally, one or more of the compounds may be mixed with other active agents.

Suitable physiologically compatible carriers may be readily selected by one of skill in the art. For example, suitable solid carriers include, among others, one or more substances which may also act as lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, starch, sugars (including, e.g., lactose and sucrose), dicalcium phosphate, cellulose (including, e.g., microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose), and kaolin.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, suspending agents, thickening agents, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil, arachis oil, corn oil, peanut oil, and sesame oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Optionally, additives customarily employed in the preparation of pharmaceutical compositions may be included in the compositions. Such components include, e.g., sweeteners or other flavoring agents, coloring agents, preservatives, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA.

Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.

Desirably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient. The unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

As described herein, a therapeutically or prophylactically useful amount of a compound is that amount of a compound which alleviates the symptoms of the disease, e.g., AD, or which prevents the onset of symptoms, or the onset of more severe symptoms. Generally, an individual dose (i.e., per unit, e.g., tablet) of a compound may be in the range from about 1 μg/kg to about 10 g/kg. In one example, an individual dose of a compound is 10 mg/kg to about 5 g/kg. In another example, an individual dose of a compound is about 1 mg/kg to about 200 mg/kg. Desirably, these amounts are provided on a daily basis. However, the dosage to be used in the treatment or prevention of a specific cognitive deficit or other condition may be subjectively determined by the attending physician. The variables involved include the specific cognitive deficit and the size, age and response pattern of the patient. For example, based upon the activity profile and potency of the compounds, a starting dose of about 10 mg per day with gradual increase in the daily dose to about 200 mg per day may provide the desired dosage level in the human.

Alternatively, the use of sustained delivery devices may be desirable, in order to avoid the necessity for the patient to take medications on a daily basis. “Sustained delivery” is defined as delaying the release of an active agent, i.e., a compound described herein, until after placement in a delivery environment, followed by a sustained release of the agent at a later time. Those of skill in the art know suitable sustained delivery devices. Examples of suitable sustained delivery devices include, e.g., hydrogels (see, e.g., U.S. Pat. Nos. 5,266,325; 4,959,217; and 5,292,515), an osmotic pump, such as described by Alza (U.S. Pat. No. 4,295,987 and U.S. Pat. No. 5,273,752) or Merck (European Patent No. 314,206), among others; hydrophobic membrane materials, such as ethylenemethacrylate (EMA) and ethylenevinylacetate (EVA); bioresorbable polymer systems (see, e.g., International Patent Publication No. WO 98/44964, Bioxid and Cellomeda; U.S. Pat. No. 5,756,127 and U.S. Pat. No. 5,854,388); other bioresorbable implant devices have been described as being composed of, for example, polyesters, polyanhydrides, or lactic acid/glycolic acid copolymers (see, e.g., U.S. Pat. No. 5,817,343 (Alkermes Inc.)). For use in such sustained delivery devices, the compounds may be formulated as described herein.

The compounds and compositions may also be packaged in a suitable container for storage, shipment, and/or in the form a kit of parts containing the compound and/or packaging.

EXAMPLES

The following examples are provided to illustrate the production and activity of representative compounds and to illustrate their performance in a screening assay. One skilled in the art will appreciate that although specific reagents and conditions are outlined in the following examples, these reagents and conditions are not a limitation on the present invention.

Example 1

4-Chloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide

Method One

A. Methyl 2-amino-3-(trifluoromethyl)-4,4,4-trifluorobutanoate

-   -   A solution of 4,4,4,4′, 4′,4′-hexafluoro-dl-valine (2.00 g, 8.89         mmol) in CH₂Cl₂:MeOH (4:1, 50 mL) was stirred under nitrogen at         0° C. TMS diazomethane (5.33 mL, 2.0 M in hexane) was added         dropwise and the resulting solution stirred for 4 hours at         25° C. After this time period, the reaction was complete by TLC         (10% MeOH:chloroform). After concentration, the resulting         residue (2.12 g, 99%) was used directly in the next reaction         without further purification.

B. Methyl 2-[(4-chloro-phenyl)sulfonylamino]-3-trifluoromethyl-4,4,4-trifluorobutanoate

-   -   A solution of methyl         2-amino-3-(trifluoromethyl)-4,4,4-trifluorobutanoate (2.12 g,         8.87 mmol) in CH₂Cl₂ (10 mL) was stirred under nitrogen at         25° C. Pyridine (10 mL, 126 mmol) was added dropwise followed by         4-chloro-benzenesulfonyl chloride (2.81 g, 13.3 mmol) in one         portion, and the resulting solution stirred for 18 hours at         25° C. After this time period, the reaction was complete by TLC         (20:80 EtOAc:PE). After quenching with H₂O, the mixture was         diluted with Et₂O (200 mL). The organic layer was washed with 1         N aq. HCl (20 mL), sat. aq. NaHCO₃ (20 mL), and brine (20 mL),         and then dried (MgSO₄). After concentration, the crude product         was purified by Biotage Flash™ 40 chromatography, eluent: 5:95         to 20:80 EtOAc:PE, to obtain methyl         2-[(4-chloro-phenyl)sulfonylamino]-3-trifluoromethyl-4,4,4-trifluorobutanoate         as a solid (1.53 g, 42%). Mass Spectrum (−ESI): 414 [M−H]⁻.

C. 4-Chloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide

-   -   A solution of LAH (0.140 g, 3.70 mmol) in Et₂O (17 mL) was         stirred under nitrogen at 0° C. To this mixture was added         dropwise methyl         2-[(4-chloro-phenyl)sulfonylamino]-3-trifluoromethyl-4,4,4-trifluorobutanoate         (1.53 g, 3.70 mmol) in Et₂O (3 mL). After stirring at this         temperature for 0.5 h, the reaction was complete by TLC (30:70         EtOAc:PE). This mixture (with efficient stirring) was quenched         with the dropwise addition of H₂O (0.140 mL), 15% aq. NaOH         (0.140 mL), and H₂O (0.420 mL) and then stirred an additional 2         hours at 25° C. The resulting slurry was dried (Na₂SO₄) and then         filtered. After concentration, the crude product was purified by         Biotage Flash™ 40 chromatography, eluent: 5:95 to 30:70         EtOAc:PE, to obtain         4-chloro-N-[(3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide         as a solid (0.657 g, 46%, racemic mixture). The title compound         (0.277 g) was then isolated as an off-white solid using chiral         HPLC [Chiralcel® AS column; 2×25 cm, 240 nm, 0.75 mL injections;         mobile phase: 12 mL/min 10% IPA in hexane/0.1% TFA (premix);         product is peak two, R_(f)=13.9, >99% purity]. Mass Spectrum         (−ESI): 383.98 [M−H]⁻.         Anal. Calc'd for C₁₁H₁₀ClF₆NO₃S: C, 34.25; H, 2.61; N, 3.63;

Found: C, 34.32; H, 2.44; N, 3.48. Method Two

A. (2S)-4,4,4-Trifluoro-2-{[(1R)-1-phenylethyl]amino}-3-(trifluoromethyl)butan-1-ol hydrochloride Salt

-   -   To a 4L plastic beaker 50.0 g (127.0 mmol, 1.0 equiv) of         4,4,4,4′,4′,4′-hexafluoro-N-[(1R)-1-phenylethyl]-L-valine         phenylmethyl ester hydrochloride (prepared analogously to the         method described in Helvetica Chimica Acta (1998), 81(1),         182-186) and 800 mL of anhydrous toluene were added. The solid         only partially dissolved. Then, 129 mL of 1.0 N NaOH was added         in portions so that the pH=7. The contents of the beaker were         transferred to a 2L separatory funnel and the aqueous (bottom)         layer was removed. The remaining (top) layer was washed with         1×350 mL of water and extracted. The toluene layer was then         dried with 52.5 g of solid Na₂SO₄ for 30 min. The solution was         then filtered and transferred to a 3L, 3-neck round bottom flask         that was capped so that the solution remained anhydrous.     -   After 24 h, the reaction flask was equipped with a magnetic         stirrer, addition funnel, and Argon inlet. The solution was         cooled with a dry ice/acetone bath for 35 min. Then, 380 mL of         1.0 M (2.99 equiv) DIBAL-toluene was quickly added over a period         of 20 min. The internal temperature never rose above −46° C. and         the bath remained constant at −79° C. The reaction was stirred         at this low temperature for an additional 40 min, the bath was         removed, and the reaction was stirred at 25° C. for 4.5 h.     -   The reaction was checked for completion by HPLC. The reaction         was cooled with an ice/water bath and then quenched by adding 26         mL of a freshly prepared solution of 10% NaOH in portions so         that the temperature never rose above 45° C. After 15 min of         stirring, the ice bath was removed and 106.3 g of NaCl and 79.5         g of Na₂SO₄ was added to the reaction flask. The solution was         stirred at 25° C. for 1 hour with a mechanical stirrer.     -   The reaction was then filtered and the remaining solids were         washed well with toluene. The filtrates were concentrated in         vacuo and 39.8 g (99%) of the free base of the title compound         was isolated as a yellow oil.     -   The HCl salt was prepared by dissolving the 39.8 g of the yellow         oil in 520 mL of Et₂O in the 2L round bottom flask. The solution         was cooled with an ice/water bath for 30 min. Then 120 mL of 1 N         HCl in Et₂O (purchased from Aldrich) was added to the solution.         After stirring at 0° C. for 20 min, the solution solidified and         ceased stirring and the solution was warmed to 25° C. and         stirred for 20 min. The solution was filtered and washed with         200-300 mL of cold Et₂O, and dried under vacuum overnight to         give 37.036 g (83%) of the title compound as a powdery white         solid. Mass Spectrum (+ESI): 316.1 [M+H]⁺.

B. (2S)-2-Amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-1-ol hydrochloride Salt

-   -   A 2L Parr bottle was flushed with N₂ and 9.374 g (0.10 g/mmol)         of 10% Pd/C was carefully added to the flask. Then, 50 mL of         anhydrous MeOH was added and the flask was carefully swirled. A         solution of 36.136 g (98.3 mmol, 1.0 equiv) of         (2S)-4,4,4-trifluoro-2-{[(1R)-1-phenylethyl]amino}-3-(trifluoromethyl)butan-1-ol         hydrochloride salt dissolved in 50 mL of MeOH was added to the         flask. The Parr bottle was flushed with more N₂, and then         capped. The heterogeneous reaction mixture was hydrogenated at         45 psi for 2 h. The reaction was checked for completion by ¹H         NMR. The reaction was worked up by filtering through a 1-inch         pad of the Celite® reagent and washing with 1.5-2 L of MeOH. The         filtrates were combined and concentrated in vacuo to give 28.56         g (100%) of         (2S)-2-amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-1-ol         hydrochloride salt as a cream-colored solid. Further         purification by triturating with 80 mL of 1:1 hexane:Et₂O can         also be performed. Mass Spectrum (+ESI): 212.1 [M+H]⁺.

C. 4-Chloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide

-   -   To a 1-L round bottom flask containing         (2S)-2-amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-1-ol         hydrochloride salt (33.96 g, 128.8 mmol) was added 500 mL of         anhydrous CH₂Cl₂. The solution was stirred at 25° C. for 15 min         and then BSA (38 mL, 155.4 mmol, 1.21 equiv) was added to the         flask. The addition of this reagent aided in dissolution of the         solid. Triethylamine (52 mL, 373.1 mmol, 2.9 equiv) was then         added to the reaction, the reaction warmed slightly, and a white         gas formed and became progressively darker orange as the         reaction progressed. Then, DMAP (4.45 g, 36.43) was added and         the reaction was stirred an additional 20 min.     -   To the reaction was then added a solution of         4-chlorobenzenesulfonyl chloride (36.225 g, 171.6 mmol, 1.33         equiv) that had been dissolved in 66 mL of anhydrous CH₂Cl₂.         Addition of this reagent caused the color of the reaction to         change from dark-brown to light yellow. The reaction was stirred         at 25° C. overnight. The reaction was checked for completion by         HPLC as well as ¹H NMR. The reaction was quenched by adding 153         mL of tetrahydrofuran (THF) and 271 mL of 5% HCl (freshly         prepared). The resulting solution was transferred to a 1 L         separatory funnel and the aqueous layer was drained off. The         resulting organic layer was washed with the following: 1×250 mL         5% NaHCO₃, 1×250 mL of H₂O, and 1×200 mL sat'd NaCl. The organic         layer was dried over Na₂SO₄, filtered, and evaporated to give         52.5 g (100%) of the impure title compound as a red-oil. A         filter chromatography (2 inches silica gel, 2 L filter funnel, 1         L size fractions, loaded onto the column with 30% EtOAc/hexanes,         eluted with a gradient of 30% EtOAc/hexanes to 100% EtOAc) gave         46.3 g of mixed fractions, and 8.0 g of pure material. The         material isolated was recombined (66.9 g) and chromatographed (2         inches silica gel, 2 L filter funnel, 1 L size fractions, loaded         onto the column absorbed onto 120 g SiO₂, and eluted with a         gradient of 10% EtOAc/hexanes to 50% EtOAc/hexanes) giving 37.2         g of pure title compound as a cream-colored solid. This material         was triturated with 83 mL of a 10% EtOAc:hexanes solution and         the resulting solid was collected by filtration and dried under         vacuum overnight, yielding 32.084 g (65%). Mass Spectrum (−ESI):         383.9 [M−H]⁻.         Anal. Calc'd for C₁₁H₁₀ClF₆NO₃S: C, 34.25; H, 2.61; N, 3.63;

Found: C, 34.32; H, 2.44; N, 3.48. Example 2

4-Chloro-N-[(1S)-4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2-trifluoro-ethyl)-butyl]-benzenesulfonamide

Method One

A. (3,3,3-Trifluoropropyl)-triphenylphosphonium Iodide

-   -   To a solution of 1-iodo-3,3,3-trifluoropropane (19.3 g, 86.1         mmol) in toluene (50 mL) at 23° C. was added triphenylphosphine         (25.8 g, 98.5 mmol). The reaction mixture was warmed to reflux         and stirred for 28 h. The resulting mixture was cooled to 0° C.         in an ice bath and filtered to collect the white solid product.         The product was washed with toluene (3×) and air-dried to afford         the pure product as white solid (33.4 g, 80%).

B. 4,4,4-Trifluoro-2-(triphenyl-λ⁵-phosphanylidene)-butyric Acid Ethyl Ester

-   -   To a suspension of (3,3,3-trifluoropropyl)-triphenylphosphonium         Iodide (105 g, 20.6 mmol) in THF (40 mL) at −78° C. was added         slowly a solution of lithium bis(trimethylsilyl)amide (1.0 M in         THF, 41.2 mL) through an addition funnel under nitrogen. The         resulting mixture was stirred at −78° C. for 15 min followed by         dropwise addition of a solution of ethylchloroformate (3.92 mL,         41.2 mmol) in THF (40 mL). The reaction mixture was then allowed         to warm up to 25° C. while stirring. The reaction mixture was         partitioned between EtOAc (300 mL) and brine (300 mL). The         organic layer was dried over Na₂SO₄ and evaporated in vacuo to         afford a crude solid which was purified by flash chromatography         (EtOAc:hexanes 1:1) to provide a light tan solid (7.18 g) in 81%         yield. Mass Spectrum (+ESI): 431 [M+H]⁺.

C. 4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-but-2-enoic Acid Ethyl Ester

-   -   To a solution of         4,4,4-trifluoro-2-(triphenyl-λ⁵-phosphanylidene)-butyric acid         ethyl ester (2.0 g, 4.65 mmol) in THF (5 mL) was added 1 mL of         trifluoroacetaldehyde hydrate (tech.). The mixture was sealed in         a pressure tube and heated at 100° C. for 3.5 h. After cooling         to 23° C., the reaction mixture was eluted through a pad of         silica gel (100 g) and Na₂SO₄ with Et₂O (100 mL) to remove the         by-products triphenylphosphine oxide and water. The eluent was         distilled to remove Et₂O and to afford the product as a         colorless liquid (1.0 g, 86%).

D. 4,4,4-Trifiuoro-2-(2,2,2-trifluoroethyl)-butyric Acid Ethyl Ester

-   -   4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-but-2-enoic acid ethyl         ester (5.0 g, 20.0 mmol) in THF (20 mL) was treated with Pd/C         (2.5 g, 5%), and H₂ (1 atm.) at 25° C. for 17 h. The reaction         mixture was filtered through a pad of the Celite® reagent,         rinsed with Et₂O (50 mL) and the filtrate was distilled to         remove Et₂O and THF to afford the product as colorless liquid         (5.0 g, 99%).

E. 4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-butan-1-ol

-   -   To a suspension of LAH (1.0 g) in Et₂O (100 mL) at 25° C. was         added slowly 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)-butyric         acid ethyl ester (5.0 g, 19.8 mmol). The resulting mixture was         stirred at reflux for 4 h. The cooled reaction mixture was         quenched by sequential addition of water (1.0 mL), 15% NaOH in         water (1.0 mL) and water (3.0 mL). After the resulting mixture         was allowed to stir at 25° C. for 17 h, Na₂SO₄ (20 g) was added         and stirring at 25° C. continued for 1 h. The resulting         suspension was filtered through a pad of the Celite® reagent and         Na₂SO₄. The filtrate was distilled to remove all solvents to         afford the desired product as a colorless liquid (1.7 g, 41%).         Mass Spectrum (−ESI): 269 [M+OAc]⁻.

F. 4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-butyraldehyde

-   -   To a solution of         4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butan-1-ol (5.0 g, 24         mmol) in CH₂Cl₂ (80 mL) was added Dess-Martin periodinane         reagent (10 g, 24 mmol). The reaction mixture was subsequently         stirred for 20 hours at 25° C. The solution was diluted with         Et₂O (200 mL) and a 1:1 mixture of 10% sodium thiosulfate and         saturated NaHCO₃ (200 mL) was added. The mixture was stirred         rapidly for 10 min until both phases were clear. The layers were         separated and the aqueous phase was extracted with Et₂O (100         mL). The combined organic layers were washed with brine (100         mL), dried over Na₂SO₄, filtered and concentrated to 50% of its         original volume to give         4,4,4-trifluoro-2-(2,2,2-trifluoro-ethyl)-butyraldehyde that was         used as is for the subsequent reaction.

G. 4-Methyl-N-[(1S)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide

-   -   To the crude organic extract of         4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde in CH₂Cl₂         (80 mL) was added titanium (IV) ethoxide (22 g, 96 mmol)         followed by (S)-(+)-toluene sulfinimide (4.64 g, 28.8 mmol) and         the solution was heated to reflux for 15 h. The mixture was then         cooled and water (30 mL) was added. The suspension was filtered         through a pad of the Celite(® reagent and the filter cake was         washed with CH₂Cl₂. The layers of the filtrate were separated.         The combined organic extracts were washed with brine, dried over         Na₂SO₄, filtered, and concentrated. The crude product was         purified by Biotage Flash™ 40 chromatography, eluent: 20:80         EtOAc-hexanes, to afford the title compound as a yellow oil         (1.12 g) in 13% yield. Mass Spectrum (−ESI): 344 [M−H]⁻.

H. 4-Methyl-benzenensulfinic acid [1S-1-cyano-4,4,4,-trifluoro-2-(2,2,2-trifluoroethyl)-butyl]amide

-   -   To diethylaluminum cyanide (1M in toluene, 3.9 mL, 3.9 mmol) in         THF (6 mL) at 0° C. was added isopropyl alcohol (300 μL, 3.9         mmol). After 15 min, this solution was added to a −78° C.         solution of         4-methyl-N-[(1S)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide         (0.903 g, 2.6 mmol) in THF (25 mL). The solution was kept at         −78° C. for 15 min and then allowed to warm slowly to 25° C.         Saturated aqueous NH₄Cl (30 mL) was added and reaction mixture         was extracted with EtOAc (3×50 mL). The combined organic layers         were washed with brine, dried over Na₂SO₄ and evaporated to a         crude oil which was purified by flash chromatography, eluent:         20:80 EtOAc:hexanes, to provide a clear oil (640 mg) in 66%         yield. Mass Spectrum (−ESI): 371 [M−H]⁻.

I. (2S)-2-Amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester

-   -   A solution of 4-methyl-benzenensulfinic acid         [1S-1-cyano-4,4,4,-trifluoro-2-(2,2,2-trifluoroethyl)-butyl]amide         (0.20 g, 0.53 mmol) in concentrated HCl (5 mL) was heated to         100° C. for 19 h. The solvent was removed in vacuo and         azeotroped with toluene (2×5 mL). The crude solid was taken up         in anhydrous methanol (5 mL), acetyl chloride (0.50 mL) was         carefully added, and the reaction was heated to reflux for 18 h.         The solvent was removed in vacuo to afford a crude product which         was partitioned between EtOAc and 2M HCl. The aqueous layer was         extracted with EtOAc. The aqueous layer was then treated with         sat. NaHCO₃ until pH>10 and extracted with EtOAc (3×10 mL). The         organic layer was dried over Na₂SO₄ and evaporated leaving an         oil (90.9 mg) in 64% yield. Mass Spectrum (+ESI): 268 [M+H]⁺.

J. (2S)-2-(4-Chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester

-   -   4-Chlorophenyl sulphonyl chloride (211 mg, 1.00 mmol) was added         to a solution of         (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic         acid methyl ester (267 mg, 1.00 mmol) and pyridine (0.45 mL,         3.00 mmol) in CH₂Cl₂ (5 mL) and the reaction was subsequently         stirred for 18h at 25° C. The solvent was removed in vacuo and         the residue was dissolved in EtOAc (20 mL). This solution was         washed with 1M HCl (2×10 mL) and brine (10 mL), dried over         Na₂SO₄ and evaporated to afford a crude oil which was purified         by flash chromatography eluting with 20:80 EtOAc:hexanes to         provide the title compound (380 mg) as an oil in 86% yield. Mass         Spectrum (−ESI): 446.0 [M−H]⁻.

K. 4-Chloro-N-[(1S)-4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2-trifluoroethyl)-butyl]-benzenesulfonamide

-   -   A solution of         (2S)-2-(4-chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic         acid methyl ester (130 mg, 0.30 mmol) in THF (5 mL) was treated         with LiBH₄ (2M THF, 0.3 mL, 0.58 mmol) for 18 hours at 25° C.         The reaction was carefully quenched by the addition of 2M HCl         and the organic solvent removed in vacuo. The aqueous layer was         extracted with EtOAc (2×10 mL). The organic layers were         combined, dried over Na₂SO₄ and evaporated to afford a crude oil         which was purified by flash chromatography eluting with 30:70         EtOAc:hexanes to provide the title compound as a white solid         (220 mg) in 63% yield. Mass Spectrum (−ESI): 412.0 [M−H]⁻.

Method Two

A. (3,3,3-Trifluoropropyl)-triphenylphosphonium Iodide

-   -   A solution of 1,1,1-trifluoro-3-iodopropane (263.1 g, 1.17 mol)         and triphenylphosphine (924.4 g, 3.52 mol) in toluene (950 mL)         was stirred at reflux for 12 h. The solid product precipitated         from the reaction mixture throughout the course of the reaction.         The reaction was allowed to cool to ambient temperature and then         cooled to ˜5° C. in an ice bath. The solid precipitate was         isolated by filtration and dried in vacuo at 25° C. to give a         white powder (526.5 g, 92%).         Anal. Calc'd for C₂₁H₁₉F₃IP: C, 51.87; H, 3.94.

Found: C, 51.99; H, 3.90.

B. 4,4,4-Trifluoro-2-(triphenyl-λ⁵-phosphanylidene)-butyric Acid Ethyl Ester

-   -   A suspension of (3,3,3-trifluoropropyl)triphenylphosphonium         iodide (194.5 g, 0.4 mol) in THF (anhydrous, 800 mL) was cooled         to −5° C. in an ice/brine bath under nitrogen. To this         suspension, lithium bis(trimethylsilyl)amide (1.0 M in THF, 800         mL, 0.8 mol) was added drop-wise over 2 h. The temperature was         maintained below 5° C. throughout the addition. The reaction         mixture was then cooled to −75° C. in a dry ice/acetone bath. To         this solution, ethylchloroforrnate (76.5 mL, 0.8 mol) was added         drop-wise over 30 min. The reaction was stirred at −75° C. for         an additional hour and allowed to warm to 25° C. overnight. The         reaction mixture was poured onto brine (1.5 L) and stirred for         30 min. The layers were separated and the organic layer was         washed with brine (200 mL). The aqueous layer was washed with         CH₂Cl₂ (2×200 mL) and the combined organics were concentrated to         a residue. This residue was redissolved in CH₂Cl₂ (500 mL),         dried over MgSO₄, and filtered through a plug of magnasol. The         solvent was reduced to a minimum (˜100 mL) in vacuo and the         product was precipitated with hexanes (250 mL). The solvent was         completely removed in vacuo and the solid product was triturated         with hexanes (500 mL). The solid was isolated by filtration and         dried overnight in vacuo at 25° C. to give a beige powder (152.8         g, 89%).         Anal. Calc'd for C₂₄H₂₂F₃O₂P: C, 66.97; H, 5.15.

Found: C, 66.37; H, 5.28.

C. 4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-but-2-enoic Acid Ethyl Ester

-   -   Trifluoroacetaldehyde hydrate (150 g, technical grade, pH 1) was         treated with stirring with solid, anhydrous sodium bicarbonate         (15 g, powder) to result in a mildly foaming suspension.         Anhydrous magnesium sulfate powder (60 g) was added, followed by         addition of MTBE (300 mL) to result in a mildly exothermic         reaction. The suspension was kept in a water bath at 10° C. for         10 min and filtered through a fluted filter funnel and washed         with MTBE (2×250 mL). The filtrate (pH 7.2) was charged into a 2         L “Parr” pressure reactor containing the starting ylide,         prepared as described in Example 2, Method 2, step B, (204 g,         0.474 mol). To the mixture was added anhydrous magnesium sulfate         powder (60 g). The reaction vessel was heated to 70-75° C. with         stirring for 15 h. The pressure in the “Parr” reactor rose to         18-21 psi. The reaction was cooled to ambient temperature and         the mixture was filtered. The filter cake was washed with MTBE.         The filtrate was distilled at 60-70 mm/Hg to remove most of the         MTBE in the first fraction and collected the remainder in the         second fraction. The pressure for the second fraction was         reduced to 20 mm/Hg to yield 121.7 g. The second fraction         (121.7 g) was redistilled at 20 mm/Hg with a bath temperature at         80° C. to yield a main fraction of a low viscosity liquid,         (103.5 g, 87%) b.p. 53-55° C. Mass Spectrum (+ESI): 251 [M+H]⁺

D. 4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-butyric Acid Ethyl Ester

-   -   4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)but-2-enoic acid ethyl         ester (225 g, 0.9 mol) was dissolved in THF (700 mL) and treated         with 5% Pd/C (17 g). The mixture was reduced by hydrogenation in         a “Parr” shaker in a 2.5 L pressure bottle at 50 psi. The         reaction was exothermic to 45° C. and was controlled by         interrupting the shaking motion of the “Parr” shaker. The         reaction was completed in approximately 2 h. The reaction         mixture was filtered through a 2-inch bed of the Solka Floce®         reagent/magnesium sulfate to give a clear, colorless solution of         the title compound (225 g in 1182 g of tetrahydrofuran,         quantitative yield). Mass Spectrum (+ESI): 253 [M+H]⁺

E. 4,4,4-Trifluoro-N-methoxy-N-methyl-2-(2,2,2-trifluoroethyl)butyramide

-   -   N,O-Dimethylhydroxylamine hydrochloride (90 g, 092 mol) was         added to a solution of         4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyric acid ethyl ester         (116.28 g, 0.46 mol) in THF (610.8 g weight of the solution).         The mixture was cooled to −15 to −20° C. with a dry ice/ acetone         bath. To the reaction mixture was added dropwise a solution of         isopropyl magnesium chloride (924 mL, 2M in THF, 1.848 mol) over         a period of 1 h, keeping the temperature at −15 to −20° C. After         the addition, the reaction was stirred at that temperature for         30 min.

The reaction was quenched by adding dropwise HCl (2N, 600 mL 1.2 mol). The reaction proceeded at a very exothermic rate for the first 50 mL. The temperature did not exceed 3° C. Initially, a thick suspension formed which subsequently became a clear solution with two layers.

The mixture was extracted with MTBE (1.5 L). The aqueous phase was re-extracted with MTBE (0.5 L). The combined organic extracts were washed with brine (2×0.5 L). The organic phase was dried over anhydrous magnesium sulfate powder, filtered and the filtrate was concentrated in vacuo at max. 35° C. to an oil of weight of 121 g. The oil was distilled at 15 mm/Hg/b.p. 64-68° C. to give the title compound as oil. Mass Spectrum (+ESI): 268 [M+H]⁺

F. 4,4,4-Trifluoro-2-(2,2,2-trifluoro-ethyl)-butyraldehyde

-   -   To a solution of         4,4,4-trifluoro-N-methoxy-N-methyl-2-(2,2,2-trifluoroethyl)-butyramide         (2.67 g, 10 mmol) in CH₂Cl₂ (10 mL), diisobutylaluminum hydride         (2.9 mL, 16 mmol) was added over 10 min at −70° C. The reaction         mixture was stirred at −70° C. for 40 min, then transferred via         a cannula to a flask containing 30 mL of 2N HCl at 0° C. 10 mL         of conc. HCl was added and the mixture was stirred at 25° C. for         30 min. Phases were split and the aqueous phase was extracted         with 5 mL of CH₂Cl₂. The combined organic phase was washed with         brine and dried over MgSO₄. NMR analysis of the solution using         an internal standard indicated formation of the title product in         65% yield. The solution was used as such for further         transformations.

G. 4-Methyl-N-[(1S)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide

-   -   To a CH₂Cl₂ solution of         4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde (92 mL;         contained 8.8 mmol of the aldehyde; prepared as described above)         titanium isopropoxide (13.4 mL, 44 mmol, 97% pure) and         (S)-(+)-p-toluenesulfinamide were added. The reaction mixture         was stirred at 40° C. for 5 h, cooled to 25° C., and poured into         a mixture of CH₂Cl₂ (100 mL) and water (50 mL) at 0° C. The         mixture was stirred at 25° C. for 1 h, then filtered through the         Celite® reagent. The phases were separated and the aqueous phase         was extracted with CH₂Cl₂. The combined organic fraction was         washed with brine, dried over MgSO₄, and concentrated. The         resultant crude mixture was dissolved in 3:7 EtOAc-heptane,         passed through a pad of silica gel, and concentrated to afford         2.11 g (69%) of the title product. Mass Spectrum (+ESI): 346         [M+H]⁺.

H. 4-Methyl-benzenensulfinic acid [1S-1-cyano-4,4,4,-trifluoro-2-(2,2,2-trifluoroethyl)-butyl]amide

-   -   THF (6 mL) and diethylaluminum cyanide (3 mL of 1 M toluene         solution, 3 mmol) were placed in a 50-mL flask. Isopropanol         (0.153 mL, 2 mmol) was added at 0° C. The mixture was stirred at         0° C. for 15 min, then transferred via a cannula to a flask         containing THF (18 mL) and         4-methyl-N-[(1S)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide         (0.69 g, 2 mmol) at −70° C. The reaction mixture was warmed up         to 25° C. and stirred for 1 h. The mixture was quenched by the         addition of 50 mL of NH₄Cl solution at 0° C. The resultant         suspension was filtered through the Celite® reagent. The Celite®         pad was washed with EtOAc. The phases were separated. The         aqueous phase was extracted with EtOAc. The combined organic         fraction was washed with brine, dried, and concentrated to         afford 0.72 g of the title product as a 10:1 mixture of         diastereomers. Mass Spectrum (+ESI): 373 [M+H]⁺.

I. (2S)-2-Amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic Acid Methyl Ester.

-   -   A solution of 4-methyl-benzenensulfinic acid         [(1S)-1-cyano-4,4,4,-trifluoro-2-(2,2,2-trifluoroethyl)-butyl]amide         (10 g, 29 mmol) in concentrated HCl (200 mL) was heated under         reflux for 15 h. The reaction was cooled to 25° C. A by-product,         toluene-4-thiosulfonic acid S-p-tolyl ester, separated from the         aqueous solution as a white crystalline solid and was filtered         off. The aqueous filtrate was concentrated in vacuo to a sticky         white solid. The crude amino acid was taken up in concentrated         HCl (200 mL) and extracted with toluene (2×50 mL). The aqueous         phase was concentrated in vacuo, co-evaporating with toluene         (4×70 mL) to give a solid compound. The amino acid was dissolved         in methanol (400 mL), treated with anhydrous HCl (4N, 100 mL)         and refluxed for 72 h. The reaction was evaporated in vacuo to a         foam (60% ester conversion by NMR). The reaction mixture was         dissolved in methanol (300 mL) and treated with ethereal HCl         (2N, 100 mL) and refluxed for 24 h. The solution was         concentrated to a solid (80% ester conversion by NMR). The crude         mixture was dissolved in water and extracted with MTBE. The         aqueous phase was basified with solid NaHCO₃ and extracted with         MTBE (2×100 mL). The organic layer was dried over MgSO₄,         filtered and concentrated in vacuo to give the title compound as         a solid. (4.6g, 62%). Mass Spectrum (+ESI): 268 [M+H]⁺.

J. (2S)-2-(4-Chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoro-ethyl)-pentanoic Acid Methyl Ester

-   -   To a solution of         (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentanoic         acid methyl ester (2.173 g, 8.14 mmol) and pyridine (1.97 mL,         24.4 mmol) in CH₂Cl₂ (15 mL) was added a solution of         4-chlorobenzenesulfonyl chloride (2.66 g, 12.2 mmol, 97% pure)         in CH₂Cl₂ (7 mL). The reaction mixture was stirred at 25° C. for         4 h, then cooled to 0° C. 15 mL of IN HCl was added followed by         10 mL of dichloromethane. The phases were separated. The organic         phase was washed with IN HCl (15 mL) and brine, dried over         Na₂SO₄, and concentrated to afford 4.1 g of crude mixture as a         yellow solid. The solids were recrystallized from heptane (14         mL) to afford 3.035 g of the title product (84% yield). Mass         Spectrum (+ESI): 442 [M+H]⁺.

K. 4-Chloro-N-[(1S)-4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2-trifluoro-ethyl)-butyl]-benzenesulfonamide

-   -   To a solution of         (2S)-2-(4-chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentanoic         acid methyl ester (2.924 g, 6.6 mmol) in THF (30 mL) was added         LiBH₄ (9.9 mL of 2M THF solution, 19.8 mmol) over 10 min at         4-6° C. The reaction mixture was stirred at 25° C. for 4 days.         Additional LiBH₄ (6.6 mL of 2M THF solution, 13.2 mmol) was         added and the reaction mixture was stirred at 25° C. for an         additional 24 h. The reaction mixture was cooled to 0° C. and         quenched by slow addition of 30 mL of 2N HCl (vigorous gas         evolution). The mixture was partially concentrated in vacuum and         extracted with EtOAc. The organic fraction was washed with         brine, dried over Na₂SO₄, and concentrated to afford 2.66 g of         crude product. The crude product was dissolved in a mixture of         EtOAc (10 mL) and heptane (3 mL) at 55° C., cooled to 25° C.,         and the resultant suspension was aged for 48 h. Heptane (27 mL)         was added, and the mixture was stirred at 25° C. for additional         48 h. The precipitate was filtered, and washed with heptane to         afford 1.962 g of the title compound (72% yield), mp:         186-187° C. Chiral HPLC: 97% ee (Chiralcel® AD column 0.46×25         cm, 10% EtOH in hexanes) HRMS calc. (for M+H): 414.0360; found:         414.0359.         Anal. Calc'd for C₁₃H₁₄ClF₆NO₃S: C, 37.54; H, 3.52; N, 3.20;

Found: C, 37.74; H, 3.41; N, 3.39. Example 3

4-Chloro-3-methoxy-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

A. 4-Chloro-3-methoxy-benzene-lithium sulfinate

-   -   To a solution of 4-bromo-1-chloro-2-methoxy benzene (1.0 g, 4.5         mmol) in Et₂O (8 mL) at −70° C. was added n-BuLi (1.6 M in         hexane, 3.4 mL, 5.4 mmol). After 2 h, a slow stream of SO₂ gas         was bubbled into the reaction mixture for 7 min, then the         mixture was stirred for 45 min. The cooling bath was removed and         the reaction was then allowed to warm up to 25° C. After 15 min         of additional stirring, the precipitate was filtered off, washed         with Et₂O and air dried to give the product as an amorphous         solid in quantitative yield. This solid was used without further         purification in the next step.

B. 4-Chloro-3-methoxy-benzene Sulfonyl Chloride

-   -   To a two phase solution of CH₂Cl₂ and distilled water (6 mL         each) was added 4-chloro-3-methoxy-benzene-lithium sulfinate         (0.90 g, 4.23 mmol). The mixture was cooled to 0° C. and, while         stirring vigorously, N-chlorosuccinamide (0.565 g, 4.23 mmol)         was added portionwise over a 5 min period. The reaction was         stirred for an addtional 1 hour then diluted with CH₂Cl₂ (25         mL). The organic phase was separated, washed with distilled         water, dried over Na₂SO₄ and evaporated in vacuo to afford the         product as a pale yellow oil (0.745 g, 73%).

C. 4-Chloro-3 -methoxy-N-(3,3,3 -trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide.

To a stirred solution of 4,4,4,4′,4′,4′-hexafluoro-d1-valinol (0.175 g, 0.83 mmol), triethylamine (0.13 mL, 0.91 mmol) and CH₂Cl₂ (4 mL) at 0° C., was added a previously dissolved mixture of 4-chloro-3-methoxy-benzene sulfonyl chloride (0.20 g, 0.83 mmol) in CH₂Cl₂ (1 mL). After 15 min, the ice bath was removed and the reaction allowed to reach 25° C. and stir for 65 h. The reaction was then diluted with CH₂Cl₂ (20 mL) and poured into a separatory funnel containing a saturated NaHCO₃ solution. The organic phase was separated, washed sequentially with IN HCl solution, distilled water, brine, dried over MgSO₄ and evaporated to afford the crude product which was purified by flash chromatography, eluent: 5:1 hexanes-ethyl acetate, to afford the product as a solid (55 mg, 16%). MS (−ESI) 414.0 ([M−H]⁻).

Anal: Calc'd for C₁₂H₁₂ClF₆NO₄S . 0.15 EtOAc C, 35.28; H, 3.10; N, 3.27. Found: C, 35.55; H, 2.80; N, 3.46. Example 4

4-Chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-3-trifluoromethyl-benzenesulfonamide

To a solution of 4,4,4,4′,4,4′-hexafluoro-d1-valinol (0.10 g, 0.47 mmol) in CH₂Cl₂ (3 mL) was added a previously dissolved mixture of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (0.132 g, 0.47 mmol) in CH₂Cl₂ (1 mL). Pyridine (77 μL, 0.95 mmol) was added and the mixture was stirred at 25° C. for 96 h. The reaction was diluted by adding CH₂Cl₂ (10 mL) and poured into a separatory funnel. It was then washed sequentially with 1 N HCl (2×), distilled water, brine, and dried over MgSO₄ and evaporated to afford the crude product which was purified by flash chromatography, eluent: 3:1 hexanes-ethyl acetate, to afford the product as a solid (35.5 mg, 17%). MS (−ESI) 452.0 ([M−H]⁻).

Anal: Calc'd for Cl₂H₉ClF₉NO₃S .0.13 Hexane C, 33.02; H, 2.35; N, 3.01. Found: C, 33.03; H, 2.10; N, 2.94. Example 5

4-Chloro-3-nitro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

To a solution of 4,4,4,4′,4′,4′-hexafluoro-d1-valinol (0.50 g, 2.37 mmol), triethylamine (0.43 mL, 3.08 mmol) and CH₂Cl₂ (17.5 mL) at 0° C. was added a previously dissolved mixture of 4-chloro-3-nitro-benzenesulfonyl chloride (0.606 g, 2.37 mmol) in CH₂Cl₂ (5 mL). After 15 min, the ice bath was removed and the reaction allowed to warm up to 25° C. After 16 h, the reaction was then diluted with CH₂Cl₂ (20 mL) and poured into a separatory funnel containing a saturated NaHCO₃ solution. The organic phase was separated, washed sequentially with 1N HCl solution, distilled water, brine, dried over MgSO₄ and evaporated to afford the crude product which was purified using Biotage Flash™ chromatography, eluent: 3:1 hexanes-ethyl acetate, to afford the product as a solid (0.134 g, 13%). MS (−ESI) 428.9 ([M−H]⁻).

Examples 6-17

3-Acetyl-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

4,4,4,4′,4′,4′-Hexafluoro-d1-valinol (70 mg, 0.33 mmol) was added to a vial and dissolved in CH₂Cl₂ (1 mL). A previously dissolved mixture of 3-acetyl-benzenesulfonyl chloride (72.5 mg, 0.33 mmol) in CH₂Cl₂ (1 mL) was added, followed by pyridine (54 μL, 0.66 mmol). The vial was installed in an orbital shaker for 72 hours at 25° C. The product was isolated from the reaction mixture using Biotage Flash™ chromatography with hexanes-ethyl acetate, 3:1 as eluent to afford the product as a solid (23.7 mg, 18%).

The following compounds (Examples 6-17, Table 1) were prepared using 3-acetyl-benzenesulfonyl chloride, 4-difluoromethoxy-benzenesulfonyl chloride, 3-difluoromethoxy-benzenesulfonyl chloride, 4-ethyl-benzenesulfonyl chloride, 4-isopropyl-benzenesulfonyl chloride, 4-methoxy-benzenesulfonyl chloride, 3-methoxy-benzenesulfonyl chloride, 4-propyl-benzenesulfonyl chloride, 4-methyl-benzenesulfonyl chloride, 3-methyl-benzenesulfonyl chloride, 3-trifluoromethyl-benzenesulfonyl chloride, 4-trifluoromethyl-benzenesulfonyl chloride, and employing the procedure outlined in the previous example.

TABLE 1

(LCMS Data*: Molecular ion retention time) R-Ph-SO₂Cl 4,4,4,4′,4′,4′-hexafluoro-dl-valinol 3-acetyl-benzenesulfonyl chloride Example 6 (392.1 [M − H]⁻); 1.390 min 4-difluoromethoxy-benzenesulfonyl Example 7 chloride (416.1 [M − H]⁻); 2.143 min 3-difluoromethoxy-benzenesulfonyl Example 8 chloride (416.1 [M − H]⁻); 2.157 min 4-ethyl-benzenesulfonyl chloride Example 9 (378.1 [M − H]⁻); 2.235 min 4-isopropyl-benzenesulfonyl chloride Example 10 (392.1 [M − H]⁻); 2.373 min 4-methoxy-benzenesulfonyl chloride Example 11 (380.1 [M − H]⁻); 1.967 min 3-methoxy-benzenesulfonyl chloride Example 12 (380.1 [M − H]⁻); 1.883 min 4-propyl-benzenesulfonyl chloride Example 13 (392.2 [M − H]⁻); 2.375 min 4-methyl-benzenesulfonyl chloride Example 14 (364.1 [M − H]⁻); 2.038 min 3-methyl-benzenesulfonyl chloride Example 15 (364.1 [M − H]⁻); 2.065 min 3-trifluoromethyl-benzenesulfonyl Example 16 chloride (418.1 [M − H]⁻); 2.250 min 4-trifluoromethyl-benzenesulfonyl Example 17 chloride (418.1 [M − H]⁻); 2.248 min *Hewlett Packard Series 1100 HPLC/MS, the Primesphere ™ C18 column, 0.2 × 3 cm column, elution gradient: 20% acetonitrile/water (0.1% HCOOH) to 100% acetonitrile (0.1% HCCOH) over 3 min at a flow rate 0.6 mL/min.

Examples 18-21

4-Cyano-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

4,4,4,4′,4′,4′-Hexafluoro-d1-valinol (60 mg, 0.28 mmol) was added to a vial and dissolved in CH₂Cl₂ (1 mL). A previously dissolved mixture of 4-cyano-benzenesulfonyl chloride (56.5 mg, 0.28 mmol) in CH₂Cl₂ (1 mL) was added, followed by triethylamine (47.5 μL, 0.34 mmol). The vial was installed in an orbital shaker for 16 hours at 10° C. The product was isolated from the reaction mixture using Biotage Flash™ chromatography with hexanes-ethyl acetate, 5: 1, as eluent to afford the product as a solid (13.7 mg, 13%).

The following compounds (Examples 18-21 Table 2) were prepared using 4-cyano-benzenesulfonyl chloride, 4-nitro-benzenesulfonyl chloride, 4-trifluoromethoxy-benzenesulfonyl chloride, 4-chloro-benzenesulfonyl chloride and employing the procedure outlined in the previous example.

TABLE 2 (LCMS Data*: Molecular ion and retention time)

R-Ph-SO₂Cl 4,4,4,4′,4′,4′-hexafluoro-dl-valinol 4-cyano-benzenesulfonyl chloride Example 18 (375.2 [M − H]⁻); 2.014 min 4-nitro-benzenesulfonyl chloride Example 19 (395.2 [M − H]⁻); 2.253 min 4-trifluoromethoxy- Example 20 benzenesulfonyl chloride (434.25 [M − H]⁻); 2.548 min 4-chloro-benzenesulfonyl Example 21 chloride (384.25 [M − H]⁻); 2.354 min *Hewlett Packard Series 1100 HPLC/MS, the Primesphere ™ C18 column, 0.2 × 3 cm column, elution gradient: 20% acetonitrile/water (0.1% HCOOH) to 100% acetonitrile (0.1% HCCOH) over 3 min at a flow rate of 0.6 mL/min.

Example 22

3,5-Difluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

A. 2-(3,5-Difluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric Acid Ethyl Ester

-   -   To a solution of 3,5-difluoro-benzenesulfonyl chloride (252 mg,         1.19 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric         acid ethyl ester (300 mg, 1.19 mmol) in CH₂Cl₂ (7 mL) was added         anhydrous pyridine (144 μL, 1.77 mmol, 1.50 equiv.) and the vial         capped and shaken for 72 h. The reaction solution was         transferred to a separatory funnel with CH₂Cl₂ (100 mL), washed         with IM citric acid solution (100 mL), water (50 mL×4), brine         (100 mL), dried (MgSO₄), filtered and evaporated to give a white         solid (300 mg, 59%). Mass Spectrum (−ESI): 427.8 [M−H]⁻

B. 3,5 -Difluoro-N-(3,3,3 -trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

-   -   To a solution of         2-(3,5-difluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric         acid ethyl ester in anhydrous THF (5 mL) at 0° C. was added 2M         LiBH₄ solution in THF (0.5 mL). The solution was allowed to warm         to 25° C. and stir for 18 h. LC-MS of a reaction aliquot         revealed unreacted starting material present. The reaction         solution was immersed in an ice bath and 2M lithium borohydride         (0.5 mL) was added and the solution allowed to warm to 25° C.         and was stirred for 18 h. This procedure was repeated once more         and, after 72 h, water was added to quench the reaction. The         solvent was removed to give a tan solid which was transferred to         a separatory funnel with EtOAc (100 mL) and washed with IM         citric acid solution (100 mL×2). The aqueous washings were         combined and extracted with EtOAc (100 mL). The organic extracts         were combined, washed with brine (100 mL), dried (MgSO₄),         filtered and evaporated to give a peach colored solid (300 mg).         This residue was adsorbed onto silica gel and purified by column         chromatography, eluting with a solution of 50% EtOAc in hexanes         to afford the alcohol (119 mg, 51%) as a white solid. Mass         Spectrum (−ESI): 358.8 [M−H]⁻

Example 23

4-Chloro-3-methylsulfanyl-N-(3,3,3-trifiuoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

A. 4-Chloro-3-methylsulfanyl-benzenesulfonic acid

-   -   To a solution of 3-amino-4-chloro-benzenesulfonic acid (5.00 g,         24 mmol) in distilled water (38 mL) and concentrated HCl (6 mL,         72 mmol) at 0° C. was added sodium nitrite (1.99 g, 28.9 mmol)         in H₂O (10 mL). After 1.5 h, the mixture was allowed to warm to         25° C. and stirred for 1.5 h. Methyl disulfide (10.7 mL, 120         mmol) was added and the mixture heated to 70° C. for 18 h. The         solvent was removed, in vacuo, to give an orange solid (16.7 g)         that was used as is in the next reaction.

B. 4-Chloro-3-methylsulfanyl-benzenesulfonyl Chloride

-   -   To a mixture of 4-chloro-3-methylsulfanyl-benzenesulfonic acid         (24 mmol) in anhydrous toluene (100 mL) at 0° C. was added         thionyl chloride (2.62 mL, 36 mmol). The ice bath was removed         and the reaction heated to 85° C. for 5 h, then 70° C. for 18 h.         Unreacted starting material was still present by LC-MS and         thionyl chloride (5 mL) was added and the reaction stirred for         18 hours at 70° C. The solvent was removed to give a black oil         (470 mg, 8%) that was used as is in the next reaction.

C. 2-(3,5-Difluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric Acid Ethyl Ester

-   -   To a vial containing a solution of         2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl         ester (179 mg, 0.708 mmol) and         4-chloro-3-methylsulfanyl-benzenesulfonyl chloride (182 mg,         0.708 mmol) in anhydrous CH₂Cl₂ (3 mL) was added pyridine (100         μL, 1.1 mmol). The vial was capped and shaken at 25° C. for         18 h. The solvent was removed, in vacuo, and the material         adsorbed onto silica gel and purified by column chromatography         eluting with CH₂Cl₂ to afford the ester (78 mg, 23%) as an amber         colored oil.

D. 4-Chloro-3 -methylsulfanyl-N-(3,3,3 -trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

-   -   To a solution of         2-(3,5-difluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric         acid ethyl ester (50 mg, 0.106 mmol) in anhydrous THF (5 mL) at         0° C. was added 2M LiBH₄ in THF (53 μL). The solution was         allowed to warm to 25° C. After 18 h, the solution was quenched         with 1N hydrochloric acid and the solvent removed in vacuo. The         remaining aqueous phase was transferred to a separatory funnel         with distilled water (100 mL) and extracted with EtOAc (100 mL).         The organic layer was removed and the aqueous phase extracted         with EtOAc (100 mL×2). The organic extracts were combined,         washed with brine (100 mL), dried (MgSO₄), filtered and         evaporated to give a clear oil which was purified by Gilson         RP-HPLC (column YMC Combiprep 50×20 mm, gradient 10-100% CH₃CN :         H₂O) to afford a white solid (11 mg, 24%). Mass Spectrum (−ESI):         431 [M−H]⁻.

Example 24

4-Chloro-3-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

A. 4-Chloro-3-fluorobenzenesulfonyl chloride

-   -   The title compound was prepared using the method of Organic         Syntheses Vol. 60, 121-124. A solution of 4-chloro-3-fluoro         aniline (5 g, 0.034 mol) in glacial HOAc (10 mL) was added         slowly to concentrated HCl (30 mL) to form a white precipitate.         The mixture was cooled in a dry ice-ethanol bath. A solution of         NaNO₂ (3.08 g, 0.045 mol) in H₂O (5 mL) was added dropwise while         stirring with a glass rod, maintaining the temperature at or         below −5° C. The mixture was stirred intermittently while in the         bath for 1 h. In a separate flask, HOAc (40 mL) was saturated         with SO₂ using a gas dispersion tube (about 15 min). To this         acetic acid solution was added cuprous chloride (0.68 g, 7         mmol), which gave a grey solution. The SO₂ was bubbled through         until the solution turned green-blue. The solution was cooled in         a dry ice-ethanol bath and the diazonium salt mixture was added         in portions while stirring with a glass rod. After the addition         was complete, the reaction was removed from the bath and allowed         to come to 0° C. over 15 to 20 min. with occasional stirring.         The reaction was poured onto ice (100 mL) and extracted with         CH₂Cl₂ (2×100 mL). The combined organic layer was washed with         saturated NaHCO₃ (3×40 mL), dried (Na₂SO₄), filtered and         concentrated to afford a golden oil. The crude product was         purified by silica gel column chromatography, eluting with a         gradient of 10% to 15% CH₂Cl₂/hexanes to afford the title         compound (5.5 g, 70%) as a golden oil. Mass Spectrum (−ESI): 209         [M−Cl+O]⁻.

B. 2-(4-Chloro-3-fluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric Acid Ethyl Ester

-   -   To a vial containing a solution of         4-chloro-3-fluorobenzenesulfonyl chloride (181 mg, 0.79 mmol)         and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl         ester (200 mg, 0.79 mmol) in anhydrous dichloroethane (3 mL) was         added pyridine (192 μL). The vial was capped and shaken for         18 h. The solvent was removed in vacuo and the residue         transferred to a separatory funnel with EtOAc (100 mL) and         washed with distilled water (100 mL×2). The organic layer was         removed and the combined aqueous washings were extracted with         EtOAc (100 mL×2). The organic extracts were combined, washed         with brine (100 mL), dried (MgSO₄), filtered, and evaporated to         give a yellow solid (220 mg). This material was adsorbed onto         silica gel and purified by column chromatography, eluent: HCCl₃,         to afford a white solid (186 mg, 53%). Mass Spectrum (+ESI): 446         [M−H]⁺.

C. 4-Chloro-3-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

-   -   2-(4-Chloro-3-fluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric         acid ethyl ester (150 mg, 0.337 mmol) was dissolved in anhydrous         THF (5 mL) and cooled to 0° C. 2M LiBH₄ in THF (168 μL in THF)         was added and the solution allowed to warm to 25° C. After 18 h,         LC-MS revealed unreacted starting ester present. Additional 2M         LiBH₄ (200 μL) was added and the solution stirred for 24 h. The         solution was cooled in an ice bath and IN hydrochloric acid was         added to quench the reaction. The solvent was removed in vacuo         and the aqueous phase transferred to a separatory funnel with         EtOAc (100 mL) and washed with distilled water (100 mL). The         organic layer was removed and the aqueous phase extracted with         EtOAc (100 mL×2). The organic extracts were combined, dried         (MgSO₄), filtered and evaporated to give a white solid (111 mg).         This material was purified by Gilson RP-HPLC (column YMC         Combiprep 50×20 mm, gradient 10-100% CH₃CN: H₂O) to afford a         white solid (63 mg, 46%). Mass Spectrum (+ESI): 401.8 [M−H]⁺.

Example 25

4-Fluoro-3-methyl-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

A. 4,4,4-Trifluoro-2-(4-fluoro-3-methyl-benzenesulfonylamino)-3-trifluoromethyl-butyric Acid Ethyl Ester

-   -   To a vial containing a solution of         4-fluoro-3-methylbenzenesulfonyl chloride (50 mg, 0.24 mmol) and         2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl         ester (61 mg, 0.24 mmol) in anhydrous dichloroethane (1 mL) was         added pyridine (58 μL, 0.719 mmol) . The vial was capped and         shaken for 18 h. The solvent was removed in vacuo and the         residue transferred to a separatory funnel with EtOAc (100 mL)         and washed with distilled water (100 mL×2). The organic layer         was removed and the combined aqueous washings were extracted         with EtOAc (100 mL×2). The organic extracts were combined,         washed with brine (100 mL), dried (MgSO₄), filtered, and         evaporated to give a white solid (66 mg). This material was         purified by Gilson RP-HPLC (column YMC Combiprep 50×20 mm,         gradient 10-100% CH₃CN: H₂O) to afford a white solid (29 mg,         28%). Mass Spectrum (−ESI): 424 [M−H]⁻.

B. 4-Fluoro-3-methyl-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide

-   -   To a solution of         4,4,4-trifluoro-2-(4-fluoro-3-methyl-benzenesulfonylamino)-3-trifluoromethyl-butyric         acid ethyl ester (29 mg, 0.068 mmol) in anhydrous THF (3 mL) at         0° C. was added 2M LiBH₄ (50 μL). The solution was allowed to         warm to 25° C. After 18 h, the solution was quenched with IN HCl         and the solvent removed in vacuo. The remaining aqueous phase         was transferred to a separatory funnel with distilled water (100         mL) and extracted with EtOAc (100 mL). The organic layer was         removed and the aqueous phase extracted with EtOAc (100 mL×2).         The organic extracts were combined, washed with brine (100 mL),         dried (MgSO₄), filtered and evaporated to give a white solid (21         mg). This material was purified by Gilson RP-HPLC (column YMC         Combiprep 50×20 mm, gradient 10-100% CH₃CN : H₂O) to afford a         white solid (14 mg, 54%). Mass Spectrum (−ESI): 382 [M−H]⁻.

Example 26

4-Fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzene sulfonamide

A. Methyl 4,4,4,4′,4′,4′-hexafluoro-d1-valinate

-   -   To a solution of 4,4,4,4′,4′,4′-hexafluoro-d1-valine (2.5 g,         11.11 mmol) in CH₂Cl₂-MeOH (4:1, 25 mL) at 0° C. was added         TMS-diazomethane (2.0 M in hexane, 45 mmol, 23 mL) dropwise. The         resulting neon greenish solution was stirred for 19 hours at         25° C. After this time period, the reaction was complete by TLC         (10% MeOH in chloroform). After concentration, the resulting         residue of methyl 4,4,4,4′,4′,4′-hexafluoro-d1-valinate (2.35 g)         was used directly in the next step without further purification.         Mass Spectrum (−ESI): 238 [M−H]⁻.

B. 3,3,3-Trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine

-   -   A solution of LiBH₄ (2M THF, 19.66 mL, 39.33 mmol) was added to         a solution of methyl 4,4,4,4′,4′,4′-hexafluoro-d1-valinate (2.35         g, 9.83 mmol) in THF (80 mL) at 0° C. The reaction was allowed         to warm to 25° C. After 19 h, the reaction was cooled to 0° C.         and 2M HCl was added to the reaction mixture very carefully         until pH<2. The organic solvent was removed in vacuo and the         aqueous layer was neutralized with sat NaHCO₃ until pH=7. The         aqueous layer was extracted with EtOAc (2×50 mL) and the organic         extracts were dried over Na₂SO₄ and concentrated to provide         3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propyl         amine as a yellow oil (1.7 g, 82% yield). The crude oil was of         sufficient purity to utilize in the subsequent reaction. Mass         Spectrum (-−ESI): 210 [M−H]⁻.

C. 4-Fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzene Sulfonamide

-   -   To a solution of         3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propyl         amine (79 mg, 0.374 mmol) in CH₂Cl₂ (1 mL) was added         triethylamine (0.1 mL, 0.749 mmol) and 4-fluorobenzenesulfonyl         chloride (80.5 mg, 0.4 mmol) in CH₂Cl₂ (1 mL). The solution was         stirred for 20 hours at 25° C. and then concentrated. EtOAc (5         mL) was added and the solution was washed with 1M HCl (1 mL),         brine (1 mL), dried over Na₂SO₄ and concentrated. The crude         solid was purified by Biotage Flash™ chromatography, eluting         with EtOAc/hexanes (1:4), to give         4-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzene         sulfonamide (2.5 mg) as a white solid.

The following compounds (Examples 26-40, Table 3) were prepared by using 4-fluorobenzenesulfonyl chloride, 3-fluorobenzenesulphonyl chloride, 2-fluorobenzenesulfonyl chloride, 3-chlorobenzenesulfonyl chloride, 2-chlorobenzenesulphonyl chloride, 4-bromobenzenesulfonyl chloride, 3-bromobenzenesulfonyl chloride, benzenesulfonyl chloride, 3,4-difluorobenzenesulfonyl chloride, 2,4-difluorobenzenesulphonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 2,3-dichlorobenzenesulfonyl chloride, 3,4-dichlorobenzenesulphonyl chloride, 3-chloro-4-fluorobenzenesulphonyl chloride, 2,3,4-trifluorobenzenesulfonyl chloride and employing the procedure outlined in Example 26.

TABLE 3

(MS Data*: Molecular ion) 3,3,3-trifluoro-2-(trifluoromethyl)- RSO₂Cl 1-(hydroxymethyl)propylamine 4-fluorobenzenesulfonyl chloride Example 26 (370 [M + H]⁺) 3-fluorobenzenesulfonyl chloride Example 27 (370 [M + H]⁺) 2-fluorobenzenesulfonyl chloride Example 28 (370 [M + H]⁺) 3-chlorobenzenesulfonyl chloride Example 29 (386 [M + H]⁺) 2-chlorobenzenesulphonyl chloride Example 30 (386 [M + H]⁺) 4-bromobenzenesulfonyl chloride Example 31 (431 [M + H]⁺) 3-bromobenzenesulfonyl chloride Example 32 (431 [M + H]⁺) benzenesulfonyl chloride Example 33 (351 [M + H]⁺) 3,4-difluorobenzenesulfonyl chloride Example 34 (388 [M + H]⁺) 2,4-difluorobenzenesulphonyl Example 35 (388 [M + H]⁺) chloride 3,5-dichlorobenzenesulfonyl chloride Example 36 (421 [M + H]⁺) 2,3-dichlorobenzenesulfonyl chloride Example 37 (421 [M + H]⁺) 3,4-dichlorobenzenesulphonyl Example 38 (421 [M + H]⁺) chloride 3-chloro-4-fluorobenzenesulphonyl Example 39 (404 [M + H]⁺) chloride 2,3,4-trifluorobenzenesulfonyl Example 40 (455 [M + H]⁺) chloride

Example 41

(S)-3,4-Dichloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzene sulfonamide

A. 2-(3,4-Dichloro-benzenesulfonylamino)-4,4,4-trifluoromethyl-butyric Acid Methyl Ester

-   -   To a solution of methyl 4,4,4,4′,4′,4′-hexafluorovalinate         (prepared according to the method of Example 26, Part A, 1.1 g,         4.6 mmol) in CH₂Cl₂ (10 mL) at 25° C. was added pyridine (0.74         mL, 9.2 mmol) dropwise followed by 3,4-dichlorobenzenesulfonyl         chloride (1.69 g, 6.90 mmol) in one portion. After 19 h, the         reaction was complete by TLC (1:4 EtOAc-hexanes). After         quenching with water (1.0 mL), the mixture was diluted with         CH₂Cl₂ (30 mL). The organic layer was washed sequentially with         IN aqueous HCl (10 mL), saturated aqueous NaHCO₃ (10 mL) and         brine (15 mL), dried over MgSO₄, filtered and concentrated to         obtain a crude oil (2.1 g). The crude product was purified by         Biotage Flash™ chromatography, eluent: 1:6 EtOAc-hexanes, to         afford         2-(3,4-dichloro-benzenesulfonylamino)-4,4,4-trifluoromethyl-butyric         acid methyl ester as a white solid (1.62 g, 42%). Mass Spectrum         (+ESI): 449 [M+H]⁺.

B. 3,4-Dichloro-N-(3,3,-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzene Sulfonamide

-   -   To a solution of         2-(3,4-dichlorobenzenesulfonylamino)-4,4,4-trifluoromethyl-butyric         acid methyl ester (1.6 g, 3.57 mmol) in THF (20 mL) was added         LiBH₄ in THF (5.82 mL, 11.64 mmol) under N₂ atmosphere at 0° C.         The reaction was allowed to warm to 25° C. After 19 h, the         reaction was cooled to 0° C., quenched with 2N HCl (slow         addition), diluted with Et₂O (40 mL). The organic layer was         washed sequentially with IN aqueous HCl (10 mL), saturated         aqueous NaHCO₃ (10 mL) and brine (15 mL), dried over MgSO₄,         filtered and concentrated to obtain a crude oil (1.3 g). The         crude product was purified by Biotage Flash™ chromatography,         eluent: 1:6 EtOAc-hexanes, to afford         3,4-dichloro-N-(3,3,-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide         as a white solid (1.13 g, 84%). The racemate was separated into         its enantiomers via chiral separation using the following         conditions: Instrument; Varian prep, column; Chiralcel® AS         column (25×0.46 cm), mobile phase; 5% 2-butanol in CO₂ (200 bar)         to obtain         (S)-3,4-dichloro-N-(3,3,-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzene         sulfonamide as a white solid (0.320 g, 21% yield). Mass Spectrum         (+ESI): 421 [M+H]⁺.

S-isomer:

HPLC Analytical purity=100% (Retention time=5.666 min)

Chiral HPLC purity=95.02% (% ee=90.03)

Example 42

3,4,5-Trifluoro-N-(3,3,3-trifluoro-1 -hydroxymethyl-2-trifluoromethyl-propyl)-benzene sulfonamide

A. 4,4,4-Trifluoro-2-(3,4,5-trifluoro-benzenesulfonylamino)-3-trifluoromethyl-butyric Acid Ethyl Ester

-   -   A solution of 3,4,5-trifluorobenzenesulfonyl chloride (0.348 mL,         2.50 mmol) in CH₂Cl₂ (5 mL) was added to a solution of         2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl         ester (0.4 g, 1.67 mmol) prepared as described (J. Med Chem.         1981, 24, 1043-1047), and pyridine (0.27 mL, 3.34 mmol) in         CH₂Cl₂ (5 mL) at 0° C. and allowed to warm to 25° C. for 19 h.         The solution was washed with 1 M HCl (1 mL), brine (1 mL), dried         over Na₂SO₄ and concentrated. The crude solid was purified by         Biotage Flash™ chromatography, eluting with EtOAc/hexanes (1:4),         to give         4,4,4-trifluoro-2-(3,4,5-trifluoro-benzenesulfonylamino)-3-trifluoromethyl-butyric         acid ethyl ester (0.63 g, 85%) as a white solid. Mass Spectrum         (+ESI): 448 [M+H]⁺.

B. 3,4,5-Trifluoro-N-(3 ,3,3-trifluoro-1 -hydroxymethyl-2-trifluoromethyl-propyl)-benzene Sulfonamide

-   -   To a solution of         4,4,4-trifluoro-2-(3,4,5-trifluoro-benzenesulfonylamino)-3-trifluoromethyl-butyric         acid ethyl ester (0.54 g, 1.207 mmol) in THF (10 mL) was added         LiBH₄ in THF (2.40 mL, 4.81 mmol) at 0° C. The reaction was         allowed to warm to 25° C. for 19 h. The reaction was cooled to         0° C., quenched with 2N HCl (slow addition), and diluted with         Et₂O (40 mL). The organic layer was washed sequentially with 1N         aqueous HCl (10 mL), saturated aqueous NaHCO₃ (10 mL) and brine         (15 mL), dried over MgSO₄, filtered and concentrated to obtain a         crude oil (0.49 g). The crude product was purified by Biotage         Flash™ chromatography, eluent: 1:7 EtOAc-hexanes, to afford         3,4,5-trifluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzene         sulfonamide as a white solid (0.150 g, 29.6%). Mass Spectrum         (+ESI): 422 [M+H]⁺.

Example 43

4-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1 -(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

A. 2-Amino-4,4,4-trifluoro-3-methyl-butyric Acid Ethyl Ester

-   -   Sodium azide (1.9 g, 28.7 mmol) and ethyl         2-bromo-3-methyl-4,4,4-trifluorobutyrate (5 g, 19.2 mmol) were         placed in DMF (20 mL) and stirred for 48 h. The mixture was         diluted with EtOAc (200 mL) and washed with brine (4×100 mL).         The organic layer was dried over Na₂SO₄ and solvent removed. The         crude oil was placed in EtOH (20 mL) with 5% Pd/C (1.6 g) and         shaken for 6 hours under H₂ (50 psi). The reaction was filtered         through the Celite® reagent and the solvent was removed         providing a clear oil (1.9 g) in 50% yield.

B. (2S,3S)-2-(4-Chloro-benzenesulfonylamino)-4,4,4-trifluoro-3-methyl-butyric Acid Ethyl Ester

-   -   A solution of 4-chlorobenzene sulphonyl chloride (1.43 g, 6.75         mmol) in CH₂Cl₂ (20 mL) was added to a solution of         2-amino-4,4,4-trifluoro-3-methyl-butyric acid ethyl ester (0.9         g, 4.5 mmol) and pyridine (1.8 mL, 22.5 mmol) in CH₂Cl₂ (10 mL).         The reaction was stirred at 25° C. for 18 h. Solvent was removed         in vacuo and the crude oil was taken up in EtOAc (50 mL). The         organic layer was washed with 1M HCl (2×15 mL) and brine (20         mL). The organic layer was dried over Na₂SO₄ and the solvent was         removed. The diastereomers were separated by flash         chromatography (20% EtOAc/hexanes) to provide diastereomer 1         (0.38 g) and diastereomer 2 (0.22 g). The 2S,3S isomer was then         obtained from diastereomer 2 by chiral HPLC (Chiralcel® AS         column 2×25 cm, 13% IPA in Hexane, 21 mL/min, second peak RT=8.6         min) to provide a white solid (86.2 mg) in 5.1% yield.

C. 4-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

-   -   A solution of lithium borohydride (2.0 M in THF, 0.23 mL) was         added to a solution of         (2S,3S)-2-(4-chloro-benzenesulfonylamino)-4,4,4-trifluoro-3-methyl-butyric         acid ethyl ester (86 mg, 0.23 mmol) in THF (5 mL) and stirred         for 12 h. Careful addition of 2N HCl (aq) was performed until         pH<2. Organic solvent was removed in vacuo. The aqueous layer         was extracted with EtOAc (2×20 mL) and organic layers were         combined and washed with brine. The organic layer was dried over         Na2SO4 and solvent removed in vacuo. The crude solid was         purified by flash chromatography (20% EtOAc/hexanes) to provide         a white solid (61 mg) in 80% yield. Mass Spectrum (−ESI): 330.0         [M−H]⁻.

Example 44

4-Chloro-N-[(1S,2R)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

A. 2-Amino-4,4,4-trifluoro-3-methyl-butyric Acid Ethyl Ester

-   -   Sodium azide (1.9 g, 28.7 mmol) and ethyl         2-bromo-3-methyl-4,4,4-trifluorobutyrate (5 g, 19.2 mmol) were         placed in DMF (20 mL) and stirred for 48 h. The mixture was         diluted with EtOAc (200 mL) and washed with brine (4×100 mL).         The organic layer was dried over Na₂SO₄ and solvent was removed.         The crude oil was placed in EtOH (20 mL) with 5% Pd/C (1.6 g)         and shaken for 6 hours under H₂ (50 psi). The reaction was         filtered through the Celite® reagent and solvent was removed         providing a clear oil (1.9 g) in 50% yield.

B. (2S,3R)-2-(4-Chloro-benzenesulfonylamino)-4,4,4-trifluoro-3-methyl-butyric Acid Ethyl Ester

-   -   A solution of 4-chlorobenzene sulphonyl chloride (1.43 g, 6.75         mmol) in CH₂Cl₂ (20 mL) was added to a solution of         2-amino-4,4,4-trifluoro-3-methyl-butyric acid ethyl ester (0.9         g, 4.5 mmol) and pyridine (1.8 mL, 22.5 mmol) in CH₂Cl₂ (10 mL).         The reaction was stirred at 25° C. for 18 h. Solvent was removed         in vacuo and the crude oil was taken up in EtOAc (50 mL). The         organic layer was washed with 1 M HCl (2×15 mL) and brine (20         mL). The organic layer was dried over Na₂SO₄ and solvent was         removed. The diastereomers were separated by flash         chromatography (20% EtOAc/hexanes) to provide diastereomer 1         (0.38 g) and diastereomer 2 (0.22 g). The 2S,3R isomer was then         obtained from diastereomer 1 by chiral HPLC (Chiralcel® AS         column 2×25 cm, 13% IPA in hexanes, 21 mL/min, second peak         RT=9.6 min) to provide a white solid (126 mg) in 7.6% yield.

C. 4-Chloro-N-[(1S,2R)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

-   -   A solution of lithium borohydride (2.0 M in THF, 0.34 mL) was         added to a solution of         (2S,3S)-2-(4-chloro-benzenesulfonylamino)-4,4,4-trifluoro-3-methyl-butyric         acid ethyl ester (126 mg, 0.34 mmol) in THF (5 mL) and stirred         for 12 h. Careful addition of 2N HCl (aq) was performed until         pH<2. Organic solvent was removed in vacuo. The aqueous layer         was extracted with EtOAc (2×20 mL) and organic layers were         combined and washed with brine. The organic layer was dried over         Na₂SO₄ and solvent removed in vacuo. The crude solid was         purified by flash chromatography (20% EtOAc/hexanes) to provide         a white solid (80 mg) in 71% yield. Mass Spectrum (−ESI): 330.0         [M−H]⁻.

Example 45

4-Chloro-N-[4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2-trifluoro-ethyl)-butyl]-benzenesulfonamide

A. 4-Methyl-N-[4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide

-   -   To the crude organic extract of         4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde, prepared         in Example 2 step F, in CH₂Cl₂ (100 mL) was added titanium (IV)         isopropoxide (4.5 g, 16 mmol) followed by mixture of (±)-toluene         sulfinimide (744 mg, 4.8 mmol) and the solution was heated to         reflux for 18 h. The mixture was then cooled and water (20 mL)         was added. The suspension was filtered through a pad of the         Celite® reagent and the filter cake was washed with CH₂Cl_(2.)         The layers of the filtrate were separated. The combined organic         extracts were washed with brine, dried over Na₂SO₄, filtered,         and concentrated. The crude product was purified by Biotage         Flash™ chromatography, eluent: 20:80 EtOAc-hexanes, to afford         the title compound as a yellow oil (420 mg) in 30% yield. Mass         Spectrum (−ESI): 344 [M−H]⁻.

B. 4-Methyl-benzenensulfinic acid [1-cyano-4,4,4,-trifluoro-2-(2,2,2-trifluoroethyl)-butyl]amide

-   -   To diethylaluminum cyanide (1M in toluene, 1.74 mL, 1.74 mmol)         in THF (3 mL) at 0° C. was added isopropyl alcohol (88 μL, 1.16         mmol). After 15 min, this solution was added to a solution of         4-methyl-N-[4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide         (0.40 g, 1.16 mmol) in THF (25 mL) at 25° C. The solution was         kept 25° C. for 2 h. Saturated aqueous NH₄Cl (3 mL) was added         and reaction mixture was extracted with EtOAc (3×10 mL). The         combined organic layers were washed with brine, dried over         Na₂SO₄ and evaporated to a crude oil which was purified by flash         chromatography 20:80 EtOAc:hexanes to provide a clear oil (259         mg) in 60% yield. Mass Spectrum (−ESI): 371 [M−H]⁻.

C. 2-Amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic Acid Methyl Ester

-   -   A solution of 4-methyl-benzenensulfinic acid         [1-cyano-4,4,4,-trifluoro-2-(2,2,2-trifluoroethyl)-butyl]amide         (0.25 g, 0.67 mmol) in concentrated HCl (5 mL) was heated to         100° C. for 19 h. The solvent was removed in vacuo and         azeotroped with toluene (2×5 mL). The crude solid was taken up         in anhydrous methanol (5 mL) and acetyl chloride (0.50 mL) was         carefully added and the reaction was heated to reflux for 18 h.         The solvent was removed in vacuo to afford a crude product which         was partitioned between EtOAc and 2M HCl. The aqueous layer was         extracted with EtOAc. The aqueous layer was then treated with         sat. NaHCO₃ until pH>10 and extracted with EtOAc (3×10 mL). The         organic layer was dried over Na₂SO₄ and evaporated leaving an         oil (108 mg) in 61% yield. Mass Spectrum (+ESI): 268 [M+H]⁺.

D. 2-(4-Chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic Acid Methyl Ester

-   -   4-Chlorophenyl sulphonyl chloride (85 mg, 0.40 mmol) was added         to a solution of         2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid         methyl ester (108 mg, 0.40 mmol) and pyridine (0.15 mL, 1.00         mmol) in CH₂Cl₂ (2 mL) and the reaction was subsequently stirred         for 18 hours at 25° C. The solvent was removed in vacuo and the         residue was dissolved in EtOAc (20 mL). This solution was washed         with 1M HCl (2×10 mL) and brine (10 mL), dried over Na₂SO₄ and         evaporated to afford a crude oil which was purified by flash         chromatography, eluting with 20:80 EtOAc:hexanes, to provide the         title compound (125 mg) as an oil in 70% yield. Mass Spectrum         (−ESI): 446.0 [M−H]⁻.

E. 4-Chloro-N-[4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2-trifluoroethyl)-butyl]-benzenesulfonamide

A solution of 2-(4-chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester (120 mg, 0.27 mmol) in THF (5 mL) was treated with LiBH₄ (2M THF, 0.3 mL) for 18 hours at 25° C. The reaction was carefully quenched by the addition of 2M HCl and the organic solvent removed in vacuo. The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, dried over Na₂SO₄ and evaporated to afford a crude oil which was purified by flash chromatography, eluting with 30:70 EtOAc:hexanes, to provide the title compound as a white solid (75 mg) in 67% yield. Mass Spectrum (−ESI): 412.0 (M−H)⁻.

Example 46

3,4-Dichloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

A. (4S)-4-Benzyl-3-[(3S)-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one

-   -   To a cooled (−78° C.) solution of         4,4,4-trifluoro-3-methyl-butyric acid (75 mmol, 11.7 g) in THF         (750 mL) was added TEA (112.5 mmol, 11.4 g, 15.7 mL) followed by         pivaloyl chloride (82.5 mmol, 9.95 g, 10.1 mL). The reaction was         stirred for 75 min, was allowed to warm up to −5° C. over 5 min,         and held at that temperature for 25 min. In a separate flask, a         solution of (S)-(—)-4-benzyl-1,3-oxazolidin-2-one (157.5 mmol,         27.9 g) in THF (300 mL) was cooled to −78° C. and n-BuLi (1.64M         in hexanes, 150 mL, 91.5 mmol) was added. After the addition was         complete, the solution was stirred for 30 min after which this         solution was cooled to −78° C. and was added via cannula to the         suspension of mixed anhydride. The reaction mixture was allowed         to warm overnight. 1N sodium bisulfate was added to the reaction         mixture. The THF was removed in vacuo. The resulting aqueous         layer was extracted with dichloromethane (DCM) and the combined         organic layers were washed with saturated NaHCO₃, dried over         Na₂SO₄, filtered, and concentrated in vacuo to give 42 g of a         light yellow viscous oil. Flash chromatography (gradient         EtOAc/hexanes) gave 24 g of a viscous oil. The oil was washed         twice with NaHCO₃, dried over Na₂SO₄, filtered, and concentrated         in vacuo to give 21 g of a viscous oil. Flash chromatography on         SiO₂ (gradient Et₂O/hexanes) provided the title compound (3.79         g, 16%) as a white solid. MS (+ESI) 316.1 m/z ([M+H]⁺).

B. (4S)-4-Benzyl-3-[((2S,3S)-2-azido-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one

-   -   A solution, cooled to −78° C., of lithium diisopropyl amide,         prepared fresh from n-BuLi (1.64M in hexanes, 13.2 mmol) and         diisopropyl amine (1.3 g, 13.2 mmol) in THF (40 mL), was added         via cannula to a precooled (−78° C.) solution of         (4S)-4-benzyl-3-[(3S)-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one         (3.79 g, 12.0 mmol) in THF (40 mL). The reaction mixture was         stirred at −78° C. for 0.5 hours after which a −78° C. solution         of trisyl azide (4.09 g, 13.2 mmol) in THF (40 mL) was added         rapidly via cannula. After 3 min, AcOH (55.2 mmol, 3.17 mL) was         added to the reaction mixture. The cooling bath was removed and         the reaction mixture was allowed to stir at room temperature         overnight. The reaction mixture was diluted with saturated NaCl         and the mixture was stirred for 30 seconds. The mixture was         extracted with CH₂Cl₂. The combined organic layers were dried         over Na₂SO₄, filtered, and concentrated in vacuo to provide a         yellow oil. Flash chromatography on SiO₂ (gradient         EtOAc/hexanes) provided the title compound (3.48 g, 81%) as a         light yellow viscous oil. MS (+ESI) m/z 331.1 [M+H]⁺

C. (4S)-4-Benzyl-3-[(2S,3S)-2-amino-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one Hydrochloride

-   -   Methanolic HCl was prepared from MeOH (20 mL) and propionyl         chloride (19.08 mmol, 1.77 g, 1.66 mL) at room temperature. A         solution of         (4S)-4-benzyl-3-[((2S,3S)-2-azido-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one         (9.54 mmol, 3.4 g) in MeOH (75 mL) was added to the methanolic         HCl solution and the reaction mixture was hydrogenated at 1 atm         over 10% Pd/C (500 mg) overnight. The reaction was filtered         through the Celite® reagent with MeOH. The solution was         concentrated in vacuo to yield a yellow solid. MeOH was added         (<5 mL) followed by Et₂O. The mixture was stirred for at least         30 min, filtered off, washed with Et₂O, and dried under vacuum         to provide the title compound as a white solid (2.58 g, 73%). MS         (+ESI) m/z 331.1 [M+H]⁺

D. (4S)-4-Benzyl-3-[(2S,3S)-2-{N-(3,4-dichlorophenylsulfonyl) }-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one

-   -   A solution of DMAP (0.945 mmol, 115 mg) and         3,4-dichlorophenylsulfonyl chloride (0.9 mmol, 221 mg, 141 μL)         in DCM (5 mL) was stirred for 15 min. To this suspension was         slowly added a cloudy solution of         (4S)-4-benzyl-3-[(2S,3S)-2-amino-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one         hydrochloride (0.45 mmol, 168 mg) in DCM (750 μL). The reaction         mixture was stirred at room temperature for 48 h. The reaction         mixture was diluted with DCM and washed with water. The organic         layer was dried over Na₂SO₄, filtered, and concentrated in         vacuo. Flash chromatography on SiO2 (gradient EtOAc/hexanes)         provided the title compound as a white powder (208 mg, 86%). ¹H         NMR 500 MHz (DMSO-d₆) d 0.98 (d, J=7.07 Hz, 3 H); 2.40-2.50 (m,         2 H); 3.00-3.10 (m, 1 H); 4.06 (dd, J=8.58 Hz, 2.55 Hz, 1 H);         4.26 (t, J=8.12 Hz, 1 H); 4.35-4.42 (m, 1 H); 5.65 (dd, J=10.6         Hz, 2.26 Hz, 1 H); 7.01 (d, J=6.61 Hz, 2 H); 7.20-7.30 (m, 3 H);         7.19-7.31 (m, 4 H); 7.74 (dd, J=8.42 Hz, 2.15 Hz, 1 H); 7.88 (d,         J=8.35 Hz, 1 H); 7.96 (d, J=2.2 Hz, 1 H); 8.90 (d, J=10.7 Hz, 1         H).

E. 3,4-Dichloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

-   -   To a solution of         (4S)-4-benzyl-3-[(2S,3S)-2-{N-(3,4-dichlorophenylsulfonyl)}-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one         (0.380 mmol, 205 mg) in dry THF (2 mL) was added LiBH₄ (2.0M in         THF, 0.762 mmol, 381 μL) dropwise at room temperature. The         reaction mixture was stirred at room temperature for 2 h. 2N HCl         was added carefully until no more foam appeared. The reaction         mixture was diluted with water and partitioned with EtOAc. The         organic layer was separated and the aqueous layer was extracted         with EtOAc. The combined organic layers were dried over Na₂SO₄,         filtered, and concentrated in vacuo to give an oil. Flash         chromatography on SiO₂ (gradient EtOAc/hexanes) provided the         title compound as a white solid (88.8 mg, 63%). MS (−ESI) m/z         364 ([M−H]⁻)

Example 47

N-[(1S,2S)-3,3,3-Trifluoro-1-(hydroxymethyl)-2-methylpropyl]-4-(trifluoromethyl)benzenesulfonamide

A. (4S)-4-Benzyl-3-[(2S,3 S)-2- {N-(4-(trifluoromethyl)benzenesulfonyl) }-3 -(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one

-   -   The title compound was prepared in a similar fashion as step D         of Example 46 using         (4S)-4-benzyl-3-[(2S,3S)-2-amino-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one         hydrochloride (0.45 mmol, 168 mg) from step C of Example 46,         DMAP (0.945 mmol, 115 mg), and         4-(trifluoromethyl)benzenesulfonyl chloride (0.9 mmol, 220 mg)         in DCM (5 mL total volume). ¹H NMR 500 MHz (DMSO-d₆) d 1.00 (d,         J=7.08 Hz, 3 H); 2.36 (d, J=6.03 Hz, 2 H); 2.98-3.10 (m, 1 H);         4.01-4.05 (m, 1 H); 4.23 (t, J=8.24 Hz, 1 H); 4.30-4.37 (m, 1         H); 5.68 (dd, J=10.6 Hz, 2.50 Hz, 1 H); 6.99 (d, J=6.73 Hz, 2         H); 7.19-7.30 (m, 3 H); 7.98 (quart, J=7.81 Hz, 4 H); 8.87 (d,         J=10.7 Hz, 1 H).

B. N-[(1S,2S)-3,3,3-Trifluoro-1-(hydroxymethyl)-2-methylpropyl]-4-(trifluoromethyl)benzenesulfonamide

-   -   The title compound was prepared in a similar fashion to step E         of Example 46 as a white solid (28.2 mg, 45%) using         (4S)-4-benzyl-3-[(2S,3S)-2-{N-(4-(trifluoromethyl)benzenesulfonyl)         }-3-(4,4,4-rifluoromethyl)butanoyl]-1,3 -oxazolidin-2-one (0.265         mmol, 130 mg) from step A of Example 47 and LiBH₄ (2.0M in THF,         0.380 mmol, 190 μL) in THF (2.7 mL total volume). MS (−ES) m/z         364.1 ([M−H]⁻)

Example 48

4-Fluoro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

-   -   A. (4S)-4-Benzyl-3-[(2S,3 S)-2-{N-(4-fluorophenylsulfonyl)         }-3-(4,4,4-trifluoromethyl)butanoyl]-1 , 3-oxazolidin-2-one     -   The title compound was prepared in a similar fashion to step D         of Example 46 using         (4S)-4-benzyl-3-[(2S,3S)-2-amino-3-(4,4,4-trifluoromethyl)butanoyl]-1,3-oxazolidin-2-one         hydrochloride (0.30 mmol, 113 mg) from step C of Example 46,         DMAP (0.63 mmol, 77 mg), and 4-fluorophenylsulfonyl chloride         (0.9 mmol, 220 mg) in DCM (1.7 mL total volume).     -   ¹H NMR 500 MHz (DMSO-d₆) d 1.00 (d, J=7.08 Hz, 3 H); 2.45-2.50         (m, 2 H); 2.95-3.05 (m, 1 H); 4.05 (dd, J =8.65 Hz, 2.38 Hz, 1         H); 4.25 (t, J =8.30 Hz, I H); 4.36-4.40 (m, 1 H); 5.64 (dd,         J=10.7 Hz, 2.49 Hz, 1 H); 7.02 (d, J=6.73 Hz, 2 H); 7.20-7.30         (m, 3 H); 7.42 (t, J=8.88 Hz, 3 H); 7.81-7.85 (m, 2 H); 8.64 (d,         J=10.7 Hz, 1 H)

B. 4-Fluoro-N-[(1S,2S)-3,3,3-trifluoro-1 -(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

-   -   The title compound was prepared in a similar fashion to step E         of Example 46 as a white solid (58 mg, 85%) using         (4S)-4-benzyl-3-[(2S,3S)-2-{N-(4-fluorophenylsulfonyl)         }-3-(4,4,4-trifluoromethyl)butanoyl]1,3 -oxazolidin-2-one (0.215         mmol, 105 mg) from step A of Example 48 and LiBH₄ (2.OM in THF,         0.430 mmol, 215 μL) in THF (1.4 mL total volume). MS (ES) m/z         314.1 ([M−H]⁻)

Example 49

Pharmacology: Aβ40/42 ELISA Assay

Compounds are diluted from DMSO stocks to 2 μM and below in a cell culture medium. Compounds are then applied to CHO cells carrying the APP-REP-NL plasmid [Sudhir et. al, J. Biol. Chem. 267:25602-25608 (1992)] for a period of 22 hours. After the conditioning period, medium is collected, diluted in assay buffer containing protein, and samples, controls, and synthetic peptide standards are incubated on a prepared ELISA plate. Using a sandwich ELISA with antibodies specifically directed against the carboxyl terminus of beta amyloid 40 or 42 [analogous to the method reported by Haugabook et al., J. Neurosci. Methods 108:171-179 (2001) but using goat anti-mouse IgGI (source: Southern Biotech) as the anchor, 6E10 as the capture antibody (Source: SENETEK), rabbit antiaβ40 and antiaβ42 (source: QCB) and APL-donkey anti-rabbit IgG (H+L, source: Southern Biotech) as the detection antibody], the effect of the compound treatment on the cellular production of extracellular beta amyloid is quantified. Cells treated with compound are subsequently incubated in cell culture medium containing MTS-formazan. After a short incubation period, MTS/medium containing plates are read in a spectrophotometer to determine the extent to which compound toxicity affected the cell's metabolism and ability to synthesize beta amyloid.

A. Materials for the Assay:

-   -   Test Samples: compound samples are supplied as 20 mM stock         solutions in a 100% DMSO solution.     -   APP-REP-NL cells: Qualified cell lines are carried from week to         week using 1:100 dilutions and are cultured in DMEM supplemented         with 1× antibiotic/antimycotic, 200μg/ml of G418 antibiotic, and         10% certified fetal calf serum. Cells are also banked in liquid         nitrogen. Periodically, beta amyloid production is assessed, and         cells are either kept in culture or replaced with progenitors at         fall expression.     -   Antibodies: Are from certified lots that have already been         qualified in this assay. Antibodies are stored in small frozen         aliquots at −80° C. that are thawed and used.

B. Criteria for activity

-   -   A compound is considered active if it has an EC₅₀ for Aβ 40         reduction of <100 μM and no toxicity at doses in the vicinity         the EC₅₀

ELISA ELISA Data Data EC₅₀ Aβ₄₀ EC₅₀ Aβ₄₂ Ex # (nM) (nM) Name 1 220 177 4-chloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 2 334 204 4-chloro-N-[(1S)-4,4,4-trifluoro-1-(hydroxymethyl)-2- (2,2,2-trifluoroethyl)butyl]benzenesulfonamide 3 9935 13847 4-chloro-3-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)- 2-(trifluoromethyl)propyl]benzenesulfonamide 4 37687 89862 4-chloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]-3- (trifluoromethyl)benzenesulfonamide 5 45973 76938 4-chloro-3-nitro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 6 13432 11220 3-acetyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 7 4461 4023 4-(difluoromethoxy)-N-[3,3,3-trifluoro-1-(hydroxymethyl)- 2-(trifluoromethyl)propyl]benzenesulfonamide 8 47937 3-(difluoromethoxy)-N-[3,3,3-trifluoro-1-(hydroxymethyl)- 2-(trifluoromethyl)propyl]benzenesulfonamide 9 7201 6751 4-ethyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 10 17718 44104 4-isopropyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 11 6807 6441 4-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 12 24102 3-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 13 17993 4-propyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 14 1504 1261 4-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 15 15068 14546 3-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 16 28119 N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]-3- (trifluoromethyl)benzenesulfonamide 17 2287 1936 N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]-4- (trifluoromethyl)benzenesulfonamide 18 90678 100780 4-cyano-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 19 27804 26845 4-nitro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 20 8508 6417 N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl- propyl)-4-trifluoromethoxy-benzenesulfonamide 21 997 932 4-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 22 5716 6336 3,5-difluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 23 22315 4-chloro-3-(methylthio)-N-[3,3,3-trifluoro-1- (hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 24 1091 1141 4-chloro-3-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 25 6635 8369 4-fluoro-3-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 26 1130 1207 4-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 27 9077 12069 3-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 28 23380 44245 2-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 29 24218 37184 3-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 30 25438 24472 2-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 31 886 905 4-bromo-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 32 19844 25335 3-bromo-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 33 6261 7021 N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl- propyl)-benzenesulfonamide 34 2224 2402 3,4-difluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 35 9766 11170 2,4-difluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 36 63950 3,5-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 37 11091 14002 2,3-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 38 4681 6551 3,4-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 39 6716 8625 3-chloro-4-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 40 32168 45374 2,3,4-trifluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2- trifluoromethyl-propyl)-benzenesulfonamide 41 5573 5369 3,4-dichloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 42 6632 5503 3,4,5-trifluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2- (trifluoromethyl)propyl]benzenesulfonamide 43 423 384 4-chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2- methylpropyl]benzenesulfonamide 44 2942 3514 4-chloro-N-[(1S,2R)-3,3,3-trifluoro-1-(hydroxymethyl)-2- methylpropyl]benzenesulfonamide 45 518 504 4-chloro-N-[4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2- trifluoro-ethyl)-butyl]-benzenesulfonamide 46 5070 4836 3,4-dichloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)- 2-methylpropyl]benzenesulfonamide 47 1402 1171 N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2- methylpropyl]-4-(trifluoromethyl)benzenesulfonamide 48 651 563 4-fluoro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2- methylpropyl]benzenesulfonamide

All publications cited in this specification are incorporated herein by reference. While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims. 

1. A method of inhibiting beta amyloid production in a subject, said method comprising delivering a compound of Formula (I), or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, to said subject, wherein Formula (I) has the structure:

wherein: R₁ through R₅ are independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, OCF₃, OCF₂H, CF₃, NO₂, CN, CH₃CO, and SCH₃; R₆ and R₇ are independently selected from the group consisting of lower alkyl and CF₃(CH₂)_(n); and n is independently selected from the group consisting of 0, 1, 2 and 3, provided that at least one of R₆ and R₇ are CF₃(CH₂)_(n).
 2. The method according to claim 1, wherein said compound is delivered orally, by injection, by inhalation, transdermally and suppository.
 3. The method according to claim 1, wherein one of R₆ or R₇ is CF₃(CH₂)_(n) and the other is CH₃.
 4. The method according to claim 1, wherein the compound is selected from the group consisting of: 4-chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide; 4-chloro-N-[(1S,2R)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide; 3,4-dichloro-N-[( 1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide; 4-fluoro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide; and N-[( 1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]-4-(trifluoromethyl)benzenesulfonamide.
 5. The method according to claim 1, wherein R₃ is halogen.
 6. The method according to claim 1, wherein R₃ is CF₃.
 7. The method according to claim 1, wherein one of R₆ or R₇ is CF₃(CH₂)_(n) where n is 1, 2 or 3 and the other is selected from lower alkyl and CF₃(CH₂)_(n), wherein n is 2 or
 3. 8. The method according to claim 1, wherein said compound has a chiral center at the C attached to the N and S-stereochemistry at the chiral center.
 9. The method according to claim 1, wherein R₁, R₂, R_(4,) and R₅ are H
 10. The method according to claim 1, wherein R₆ and R₇ are CF₃(CH₂)_(n) and n is
 0. 11. The method according to claim 1, wherein said compound is selected from the group consisting of: 4-chloro-N-[(1S)-3,3,3 -trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-chloro-N-[(1S)-4,4,4-trifluoro-1-(hydroxymethyl)-2-(2,2,2-trifluoroethyl)butyl]benzenesulfonamide; 4-chloro-3-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-chloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-3-nitro-N-[3,3,3 -trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 3-acetyl-N-[3 ,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-(difluoromethoxy)-N-[3,3,3-trifluoro-1-(hydroxym ethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 3-(difluoromethoxy)-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-ethyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-isopropyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 3-methoxy-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-propyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 3-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]-3 -(trifluoromethyl)benzenesulfonamide; N-[3,3,3-trifluoro-1-(hydroxyrnethyl)-2-(trifluoromethyl)propyl]-4-(trifluoromethyl)benzenesulfonamnide; 4-cyano-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 4-nitro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-4-trifluoromethoxy-benzenesulfonamide 4-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3,5-difluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-chloro-3-(methylthio)-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-chloro-3-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifiuoromethyl)propyl]benzenesulfonamide; 4-fluoro-3-methyl-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonairide; 4-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 2-fluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 2-chloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 4-bromo-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3-bromo-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3,4-difluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 2,4-difluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3,5-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 2,3-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3,4-dichloro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3-chloro-4-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 2,3,4-trifluoro-N-(3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-benzenesulfonamide; 3,4-dichloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide; 4-chloro-N-[4,4,4-trifluoro-1-hydroxymethyl-2-(2,2,2-trifluoro-ethyl)-butyl]-benzenesulfonamide; and 3,4,5-trifluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide.
 12. The method according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of salts of bases.
 13. The method according to claim 11, wherein the salts of bases are selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and mixtures thereof.
 14. The method according to claim 1, wherein said compound of Formula (I) is in a composition.
 15. The method according to claim 14, wherein said composition is delivered orally, by injection, by inhalation, transdermally and suppository.
 16. A method of treating a disease selected from the group consisting of Alzheimer's disease, anmyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, mild cognitive impairment (MCI) and Down's syndrome, in a subject, said method comprising the step of administering a compound of Formula (I) , or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, to said subject in an amount sufficient to alleviate the symptoms or progress of said disease, wherein Formula (I) has the structure:

wherein: R₁ through R₅ are independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, OCF₃, OCF₂H, CF₃, NO₂, CN, CH₃CO, and SCH₃; R₆ and R₇ are independently selected from the group consisting of lower alkyl and CF₃(CH₂)_(n); and n is independently selected from the group consisting of 0, 1, 2 and 3, provided that at least one of R₆ and R₇ are CF₃(CH₂)_(n).
 17. The method according to claim 16, wherein said compound of formula (I) is in a composition.
 18. The method according to claim 16, wherein said compound of formula (I) is present in an amount sufficient to alleviate the symptoms or progress of said disease.
 19. A pharmaceutical kit comprising a container comprising a pharmaceutical composition, wherein said pharmaceutical composition comprises a compound of Formula (I), or pharmaceutically acceptable salts and/or hydrates or prodrugs thereof:

wherein: R₁ through R₅ are independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, OCF₃, OCF₂H, CF₃, NO₂, CN, CH₃CO, and SCH₃; R₆ and R₇ are independently selected from the group consisting of lower alkyl and CF₃(CH₂)_(n); and n is independently selected from the group consisting of 0, 1, 2 and 3, provided that at least one of R₆ and R₇ are CF₃(CH₂)_(n). 